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Summary Objectives To evaluate the role of 18-fluoro-2-deoxyglucose positron emission tomography–computed tomography ( 18 F-FDG-PET–CT) in the diagnosis of infectious endocarditis (IE). Methods We retrospectively examined 27 consecutive patients who were admitted to the Infectious Diseases Department of Tor Vergata University Hospital between 2009 and 2013 with a suspicion of IE. The final IE diagnosis was defined according to the modified Duke criteria, and the microbiological and diagnostic results were collected for each patient. Results Twenty out of 27 patients had a suspected prosthetic valve endocarditis (PVE) and seven had a suspected native valve endocarditis (NVE). Twenty-five out of 27 patients (92%) had a confirmed diagnosis of IE (18/25 PVE and 7/25 NVE); 16 had a positive echocardiography evaluation and 16 had positive 18 F-FDG-PET–CT findings. Echocardiography showed a higher sensitivity as a diagnostic tool for the detection of IE compared to 18 F-FDG-PET–CT (80% vs. 55%). However, a greater number of PVE had positive 18 F-FDG-PET–CT results compared to those with positive echocardiography findings (11/13 vs. 9/13), and overall 89% (16/18) of confirmed PVE resulted 18 F-FDG-PET–CT positive. Analyzing only the cases who underwent transoesophageal echocardiography, 18 F-FDG-PET–CT showed a sensitivity of 85% in PVE (vs. 69% for echocardiography and 77% for the Duke criteria). All seven patients with NVE had a positive echocardiography and negative 18 F-FDG-PET–CT findings ( p Conclusions The results of this study further highlight the limitations of echocardiography in the diagnosis of PVE and the potential advantages of 18 F-FDG-PET–CT in these cases.