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Background: Inflammation of unknown origin (IUO) is a challenging situation in internal medicine. Objectives: To describe the final diagnoses in IUO and assess the helpfulness of 18F‐fluorodesoxyglucose positron emission tomography with computerized tomography (18F‐FDG‐PET/CT) in the diagnosis strategy. Results: A total of 317 IUO patients with 18F‐FDG‐PET/CT were enrolled. A diagnosis was reached in 228 patients: noninfectious inflammatory diseases (NIID) (37.5%), infectious diseases (18.6%), malignancies (7.9%), and non‐systemic‐inflammatory miscellaneous diseases (7.9%). The two leading causes of NIID were polymyalgia rheumatica and giant cell arteritis. 18F‐FDG‐PET/CT results were classified as true positive in 49.8% of patients and contributory in 75.1% of overall IUO patients (after the complete investigation set and a prolonged follow‐up). In multivariate analysis, only C‐reactive protein minimum level (≥50 mg/L) was associated with the contributory status of 18F‐FDG‐PET/CT. Conclusion: Within the wide spectrum of IUO underlying diseases, 18F‐FDG‐PET/CT is helpful to make a diagnosis and to eliminate inflammatory diseases. Obese patients constitute a specific group needing further studies. [ABSTRACT FROM AUTHOR]