Infective endocarditis (IE) as a diagnosis remains challenging, particularly in prosthetic valve endocarditis (PVE). This study evaluates the diagnostic utility of ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) in patients with suspected IE. Seventy patients with suspected IE underwent clinical, microbiological, echocardiographic, and ¹⁸F-FDG PET/CT evaluation. Diagnostic performance of PET/CT was assessed against clinical classification based on modified Duke criteria. Definitive PVE was diagnosed in 18 patients (26%), while 52 (74%) had possible IE. PET/CT reclassified 13 patients from possible to definite IE, demonstrating an overall sensitivity of 83.3%, specificity of 93.7%, positive predictive value (PPV) of 83.3%, and negative predictive value (NPV) of 93.7%. Excluding native valve endocarditis cases, sensitivity and specificity increased to 94.1% and 95.7%, respectively. PET/CT detected septic emboli in five patients and incidental malignancies in three cases, underscoring its role in comprehensive patient evaluation. False-negative results were mostly observed in early post-surgical PVE and native valve endocarditis. PET/CT also identified alternative diagnoses in patients reclassified as rejected IE. ¹⁸F-FDG PET/CT provides high diagnostic accuracy for suspected PVE, significantly aiding reclassification of ambiguous cases and detection of extracardiac complications and malignancies. Its integration into diagnostic algorithms may improve clinical management and outcomes in complex IE cases.