Abstract Objectives: Fever of unknown origin (FUO) is dynamic in its origin and will be an ongoing challenge to the clinician because of shifting disease epidemiology. Here we present a series of patients with classical FUO admitted to an infectious diseases department during a 5-y period, with an emphasis on the diagnostic utility of (18)F-fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT) in present-day cases of FUO. Methods: Patient records were reviewed retrospectively. Results: A final diagnosis was achieved for 31 of the 52 cases (60%). The final diagnoses of these 31 cases and their distribution in the respective diagnostic categories were: infections 32% (10/31), non-infectious inflammatory disease 55% (17/31), and malignancy 13% (4/31). In our study PET/CT successfully identified an infectious, inflammatory, or neoplastic cause of fever in 10 of the 22 patients (45%) who underwent this scan. Conclusions: During the past decade the proportion of non-infectious inflammatory diseases in FUO series has increased. Based on our findings we recommend: (1) a PET/CT scan be performed early in the diagnostic work-up of patients with FUO, and (2) restraint in performing invasive procedures in patients with FUO in whom no cause of fever has been determined during diagnostic work-up.