This review focuses on the diagnostic value of hybrid F18-FDG Positron Emission Tomography/Computerized tomography (PET/CT) in fever of unknown origin (FUO) and inflammation of unknown origin (IUO). Due to the wide range of possible causes both FUO and IUO remain a clinical challenge for both patients and physicians. In addition, the aetiology of IUO shows the same variation in diseases as the FUO spectrum and probably requires the same diagnostic approach as FUO. There are numerous historically used diagnostic approaches incorporating invasive and non-invasive, and imaging techniques, all with relative high specificity but limited sensitivity. This hampers the generalization of these diagnostic approaches. However, recently published reports show that F18-FDG PET/CT in FUO and IUO has a high sensitivity and a relative non-specificity for malignancy, infection and inflammation. This makes F18-FDG PET/CT an ideal diagnostic tool to start the diagnostic process and to guide subsequent focused diagnostic approaches with higher specificity. In addition, F18-FDG PET/CT has a relative high negative predictive value. Therefore F18 FDG PET/CT should be incorporated in the routine diagnostic work-up of patients with FUO and IUO, preferably at an early stage in the diagnostic process. 1. Introduction 1.1. Definition of Fever of Unknown Origin Fever of unknown origin (FUO) was first used by Kiefer and Leard in their book “prolonged and perplexing fevers”. In their seminal article from 1961 Petersdorf and Beeson defined (FUO) as: (1) an illness of at least 3 weeks’ duration, (2) with fever; body temperature higher than 38.3°C (101°F) on several occasions, and (3) no established diagnosis after 1 week of hospital investigation [1]. A period of 3 weeks was chosen to eliminate self-limited viral illnesses and to allow sufficient time to complete the appropriate diagnostic procedures. Since 1961 health care has shifted from inpatient oriented healthcare to a more outpatient setting, and in response to the increasing sophistication of medical technology, Durack and Street proposed a change towards the required duration of investigation before qualifying a fever as FUO; at least 3 days in hospital or at least three outpatient visits [2]. 1.2. Aetiology of FUO Although the definition of FUO suggests that the fevers remain of unknown origin, most of the FUOs have a pathophysiological basis. Based on these pathophysiological disorders, the spectrum of FUOs may be divided into four general categories: (1) infections, (2) malignancies, (3) noninfectious inflammatory diseases,
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