Determining the cause of fever of unknown origin (FUO) often proves challenging to attending physicians and the role of conventional imaging in this setting has been uncertain. In this retrospective study, we examined the role of fluorine-18 fluorodesoxyglucose-positron emission tomography ((18)F-FDG-PET) compared to computed tomography (CT) in diagnosing the potential etiology of FUO. To accomplish this task, we identified patients with FUO who underwent (18)F-FDG-PET for detecting the source of fever. Twenty-four patients (16 males and 8 females, age range = 17-80, mean age = 49.5) were examined with (18)F-FDG-PET of which 18 were also assessed with a diagnostic CT (within 3 weeks, mean interval = 7.5 days). The PET and CT findings were reviewed and the presence of focal (18)F-FDG uptake or gross CT lesions was considered a potential site causing FUO. Of patients who underwent PET alone, ⅚ were reported as positive. Of the 18 who had both PET and diagnostic CT, PET was positive in 18 and CT was positive in only 7 cases. Of positive findings on PET, etiologies included infection (11), non-infectious inflammation (8), lymphoma (3), and other cancers (1). Of positive findings on CT, etiologies included infection (3), lymphoma (1), non-infectious inflammation (2) and other cancers (1). Importantly, we found no cases with positive CT and negative PET findings. In conclusion, accordingly to our findings, (18)F-FDG-PET appears to be of great value in assessing patients with FUO, especially when caused by infection or inflammation. Fluorine-18 FDG-PET is more sensitive than diagnostic CT in detecting and localizing diseased sites, and is the optimal imaging modality to evaluate patients with FUO.