What is the most common cause of fever of unknown origin?

September 26, 2025 •

4 min read

According to several medical studies, infectious diseases are a leading category of classic FUO, though this can vary by region and patient population. Pinpointing the answer to the question, "What is the most common cause of fever of unknown origin?" is a complex process for clinicians.

Quick Summary

Infectious diseases are the most common cause of fever of unknown origin, followed by malignancies and non-infectious inflammatory disorders. A definitive diagnosis often requires an extensive and targeted medical investigation, and in a significant number of cases, a cause is never identified.

Key Points

Infections are the most common cause: A significant percentage of FUO cases are caused by infections, though often atypical ones like extrapulmonary tuberculosis or hidden abscesses.
Malignancies are a major concern: Lymphoma, leukemia, and renal cell carcinoma are prominent non-infectious causes of FUO.
Inflammatory diseases are key: Conditions like Adult Still's disease and giant cell arteritis are also significant contributors, particularly in older patients.
Diagnosis is challenging: An FUO requires a comprehensive, systematic investigation based on clinical clues rather than a shotgun approach to testing.
Many cases go undiagnosed: Despite extensive workups, a notable percentage of FUO cases resolve on their own without a clear diagnosis, and the prognosis is usually good.
Miscellaneous factors exist: Drug-induced fever, blood clots, and inflammatory bowel disease are other, less frequent causes to consider.
Treatment is dependent on cause: Empiric treatment (treatment without a clear diagnosis) should be avoided unless the patient is immunocompromised or critically ill.

Understanding Fever of Unknown Origin (FUO)

Fever of unknown origin, commonly known as FUO, is a challenging diagnostic puzzle for healthcare providers. It is defined as a persistent fever, typically lasting more than three weeks, without an obvious cause despite extensive initial evaluation. The medical landscape has evolved significantly, leading to changes in the classic causes. While once common conditions like tuberculosis are now more readily diagnosed, FUO still represents a broad spectrum of illnesses, often presenting in unusual ways.

Infections: The Leading Culprit

Despite advances in diagnostics, infectious diseases remain the single most common cause of classic FUO in many regions, accounting for a significant portion of all cases. These are often common infections that manifest atypically, making them difficult to diagnose. Key examples of infectious causes include:

Extrapulmonary Tuberculosis: Infections in sites other than the lungs, such as the lymph nodes, abdomen, or bones, can cause prolonged fever and be notoriously difficult to detect with standard tests.
Abscesses: Hidden pockets of infection, particularly abdominal, pelvic, or dental abscesses, can cause persistent fever without clear localizing symptoms.
Endocarditis: An infection of the inner lining of the heart or its valves, subacute bacterial endocarditis can present with a persistent fever and a new heart murmur, among other non-specific signs.
Viral Infections: Certain viral illnesses, like Cytomegalovirus (CMV) or Epstein-Barr virus (EBV), can cause prolonged fever, even in patients with normal immune systems.

Malignancies to Consider

Neoplasms, or cancerous growths, are the second most common category of FUO, particularly in certain demographics. The fever in these cases is often a paraneoplastic syndrome, meaning it's a symptom of the cancer rather than an infection. Common malignancies linked to FUO include:

Lymphoma: Both Hodgkin and non-Hodgkin lymphoma are frequently associated with FUO, sometimes presenting with night sweats and unexplained weight loss.
Leukemia: Certain types of leukemia can cause persistent fever as a result of abnormal blood cell production.
Renal Cell Carcinoma: This type of kidney cancer can lead to fever without other urinary tract symptoms.

Non-Infectious Inflammatory Conditions

Systemic rheumatic diseases and other inflammatory conditions are another major group of FUO causes, particularly prevalent in older adults in high-income countries. These autoimmune disorders cause the body's immune system to attack its own tissues, leading to widespread inflammation and fever. Examples include:

Adult Still’s Disease: This is a rare inflammatory type of arthritis characterized by a high fever, joint pain, and a salmon-colored rash.
Giant Cell Arteritis (Temporal Arteritis): Primarily affecting older patients, this inflammation of the arteries can cause headaches, jaw pain, and visual disturbances in addition to fever.
Systemic Lupus Erythematosus (SLE): This autoimmune disease can cause a wide array of symptoms, with persistent fever being a possibility.

The Diagnostic Challenge

Diagnosing FUO is a process of systematic elimination guided by a patient's history and physical exam. Unlike a typical fever, which resolves quickly, FUO requires a comprehensive and often prolonged investigation. The approach is not a one-size-fits-all, and clinicians must resist the temptation to order a barrage of non-specific tests without a solid hypothesis.

Key Diagnostic Tools

Detailed History and Physical: Repeated examinations are crucial, looking for subtle clues that may have been missed initially, such as a heart murmur or faint rash.
Imaging: Computed tomography (CT) scans and positron emission tomography (PET) scans are vital for locating occult infections or tumors.
Biopsies: In some cases, a biopsy of a suspicious lymph node, liver tissue, or bone marrow is necessary for a definitive diagnosis.
Blood Cultures and Serology: Advanced testing for slow-growing bacteria or specific viral antibodies can provide answers that standard blood work misses.

Other Miscellaneous Causes

A final, diverse category of FUO includes a range of less common conditions. These can include:

Drug-Induced Fever: Certain medications, such as some antibiotics and antihistamines, can cause a fever as a side effect. This is often a diagnosis of exclusion and resolves after the medication is stopped.
Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE): Blood clots in the legs or lungs can sometimes cause a persistent fever.
Crohn's Disease: This inflammatory bowel disease can be a source of FUO.
Factitious Fever: A very small percentage of FUO cases are self-induced by the patient.

Comparison of FUO Categories


Category	Typical Percentage of Cases	Common Examples	Diagnostic Clues	Prognosis (if undiagnosed)
Infections	20-40%	Extrapulmonary TB, Abscesses, Endocarditis	Travel history, exposure, specific lab markers	Variable, dependent on infection
Malignancies	20-30%	Lymphoma, Leukemia, Renal Cell Carcinoma	Weight loss, night sweats, enlarged lymph nodes	Serious, requires treatment
Inflammatory	10-30%	Adult Still's Disease, Giant Cell Arteritis	Joint pain, rash, age (>65 for GCA)	Chronic, can be managed
Miscellaneous	10-20%	Drug-induced fever, DVT, Crohn's	Medication changes, specific symptoms	Often resolves after cause is addressed
Undiagnosed	5-15%	No identifiable cause	Spontaneous resolution	Generally good

What Happens When a Cause Isn't Found?

It is a common scenario for a significant percentage of FUO cases to remain undiagnosed, even after exhaustive testing. For most of these patients, the fever resolves on its own over time, and they have a good long-term prognosis. The body's immune system may have fought off an atypical, self-limiting infection, or the cause was simply too subtle to detect. For patients who continue to experience fever, a watch-and-wait approach may be taken while monitoring for new symptoms.

Conclusion

The medical detective work required to solve a fever of unknown origin is complex, but the initial search should heavily consider infectious diseases. While infections remain the most common cause, clinicians must also systematically evaluate for malignancies, inflammatory conditions, and a host of miscellaneous factors. Patience and a targeted diagnostic approach are key, as many fevers of unknown origin ultimately resolve without a definitive diagnosis or serious consequence. For more information on this complex topic, consult the American Academy of Family Physicians website.

Frequently Asked Questions

A fever of unknown origin (FUO) is defined as a fever lasting for more than three weeks, with a temperature of 101°F (38.3°C) or higher on several occasions, and no diagnosis established after an initial, intensive evaluation.

While infections are a leading cause across age groups, non-infectious inflammatory diseases, such as giant cell arteritis and polymyalgia rheumatica, are more frequently diagnosed as the cause of FUO in patients over 65 years old.

Infections that cause FUO often have atypical presentations and can include extrapulmonary tuberculosis, hidden abscesses (abdominal, pelvic), endocarditis (heart valve infection), and certain viral illnesses like CMV or EBV.

Yes, cancer is a significant cause of FUO. The most common types of cancer associated with FUO are lymphomas, leukemia, and renal cell carcinoma.

Diagnosis involves a meticulous process starting with a detailed patient history and repeated physical exams. This is followed by targeted tests, which may include advanced imaging (CT, PET scans), specialized blood cultures, and biopsies if warranted by clinical clues.

If the cause of FUO is never found, the prognosis is often good, and the fever typically resolves on its own over time. A watch-and-wait approach is often followed for patients who remain clinically stable.

While FUO can be caused by serious conditions, it is important to remember that many cases resolve spontaneously without a clear diagnosis. A thorough evaluation by a healthcare professional is the best way to address concerns and determine the appropriate course of action.