Objectives: To evaluate the role of 18-fluoro-2-deoxyglucose positron emission tomography–computed tomography (18F-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 18F-FDG-PET–CT findings. Echocardiography showed a higher sensitivity as a diagnostic tool for the detection of IE compared to 18F-FDG-PET–CT (80% vs. 55%). However, a greater number of PVE had positive 18F-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 18F-FDG-PET–CT positive. Analyzing only the cases who underwent transoesophageal echocardiography, 18F-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 18F-FDG-PET–CT findings (p < 0.001). Conclusions: The results of this study further highlight the limitations of echocardiography in the diagnosis of PVE and the potential advantages of 18F-FDG-PET–CT in these cases.