Few clinical problems generate such a wide differential diagnosis as pyrexia (fever) of unknown origin. The initial definition proposed by Petersdorf and Beeson in 1961,¹ later revised, is "a fever of 38.3°C (101°F) or more lasting for at least three weeks for which no cause can be identified after three days of investigation in hospital or after three or more outpatient visits." ²⁻⁴Essentially the term refers to a prolonged febrile illness without an obvious cause despite reasonable evaluation and diagnostic testing. A fever that is not self limiting for which no cause can be found can become a source of frustration for both patient and doctor. There is little consensus on how such patients should be investigated, although recent prospective studies have evaluated diagnostic protocols to suggest approaches to investigation. ³⁵⁶ We discuss evidence from epidemiological and diagnostic studies and suggest an approach to investigating and managing pyrexia of unknown origin. Immunocompromised individuals, those with HIV infection, and patients admitted to hospital for other reasons with persistent or unexplained fever represent distinct subgroups in which the likely causes, diagnosis, and treatment of pyrexia usually differ from those in patients who are not immunocompromised. We do not discuss these subgroups in this review other than to provide definitions of pyrexia of unknown origin in different groups of patients (see box 1).