Fever of unknown origin (FUO) often is defined as a fever greater than 38.3 degrees C on several occasions during at least 3 weeks with uncertain diagnosis after a number of obligatory tests. In general, infection accounts for approximately one-fourth of cases of FUO, followed by neoplasm and noninfectious inflammatory diseases. No diagnosis is reached in up to 50% of cases. Scintigraphic methods, such as (67)Ga-citrate, labeled leukocytes, and (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET), are often used in the diagnosis of FUO. In FUO, FDG-PET appears to be of great advantage because malignancy, inflammation, and infection can be detected. FDG-PET does not seem to contribute to a final diagnosis in patients with normal erythrocyte sedimentation rate and C-reactive protein. Image fusion combining PET and computed tomography facilitates anatomical localization of increased FDG uptake and better guiding for further diagnostic tests to achieve a final diagnosis. In conclusion, the body of evidence on the utility of FDG-PET in patients with FUO is growing and FDG-PET will probably become the preferred diagnostic procedure, especially when a definite diagnosis cannot easily be achieved. Because of favorable characteristics of FDG-PET, conventional scintigraphic techniques may be replaced by FDG-PET in institutions in which PET is available.