Objective: To explore the diagnostic contribution of the 18F-FDG-PET/CT in a population of patients with classical fever of unknown origin (FUO), to pinpoint its place in the diagnostic decision tree in a real-life setting, and to identify the factors associated with a diagnostic 18F-FDG-PET/CT. Method: All adult patients (aged ≥ 18 years) with a diagnosis of classical FUO who underwent an 18F-FDG-PET/CT in the University Hospital of Montpellier (France) between April 2012 and December 2017 were included. True positive 18F-FDG-PET/CT, which evidenced a specific disease causing FUO, were considered to be contributive. Results: Forty-four patients with FUO have been included (20 males, 24 females; mean age 57.5 ± 17.1 years). Diagnoses were obtained in 31 patients (70.5%), of whom 17 (38.6%) had non-infectious inflammatory diseases, 9 had infections (20.5%), and 3 had malignancies (6.8%). 18F-FDG-PET/CT was helpful for making a final diagnosis (true positive) in 43.6% of all patients. Sensitivity and specificity levels were 85% and 37%, respectively. A total of 135 investigations were performed before 18F-FDG-PET/CT, mostly CT scans (93.2%) and echocardiography (59.1%), and 108 after 18F-FDG-PET/CT, mostly biopsies (including the biopsy of a temporal artery) (25%) and MRIs (34%). In multivariate analysis, the hemoglobin level was significantly associated with a helpful 18F-FDG-PET/CT (p = 0.019, OR 0.41; 95% CI (0.20–0.87)), while the CRP level was not associated with a contributive 18F-FDG-PET/CT. Conclusion: 18F-FDG-PET/CT may be proposed as a routine initial non-invasive procedure in the diagnostic workup of FUO, especially in anemic patients who could be more likely to benefit from 18F-FDG-PET/CT.