We describe the diagnostic contribution of [(18)F]fluoro-deoxyglucose (FDG) positron emission tomography (PET) scan in 58 consecutive cases of fever of unknown origin (FUO) and compare this new approach with gallium scintigraphy. This investigation was performed from March 1996 through October 1998 at Gasthuisberg University Hospital in Leuven, Belgium. A final diagnosis was established for 38 patients (64%). Forty-six FDG-PET scans (79%) were abnormal; 24 of these abnormal scans (41% of the total number of scans) were considered helpful in diagnosis, and 22 (38% of the total number) were considered noncontributory to the diagnosis. In a subgroup of 40 patients (69%), both FDG-PET and gallium scintigraphy were performed. FDG-PET scan and gallium scintigraphy were normal in 23% and 33% of these cases, respectively; helpful in diagnosis in 35% and 25%, respectively; and noncontributory in 42% each. All foci of abnormal gallium accumulation were also detected by use of an FDG-PET scan. We conclude that FDG-PET is a valuable second-step technique in patients with FUO because it yielded diagnostic information in 41% of the patients in whom the probability of a definite diagnosis was only 64%. FDG-PET scan compares favorably with gallium scintigraphy for this indication. Because of the quick results (within hours instead of days), FDG-PET scan may replace gallium scintigraphy as a radiopharmaceutical for the evaluation of patients with FUO.