18 F-FDG PET/CT has recently been added as a major criterion in the ESC 2015 infective endocarditis (IE) guidelines. We and others have demonstrated that PET/CT was useful in patients with suspected prosthetic valve and cardiac device IE. However, the sensitivity and specificity of ESC classification is unknown in patients with NVIE. 1. Primary objective: to assess the value of the new ESC criteria including 18 F-FDG PET/CT in native valve infective endocarditis (NVIE). 2. Secondary objectives: – to determine the usefulness of PET/CT concerning embolic or neoplastic detection; – to describe a new PET/CT feature, i.e. the diffuse splenic uptake. Between 2012 and 2017, 75 patients with suspected NVIE were prospectively included, after exclusion of patients with uninterpretable or not feasible PET/CT. Using the expert consensus of the Endocarditis Team after a 3-month follow-up as gold standard, 63 IE were confirmed and 12 were rejected. Significant valvular uptake by PET/CT (major criterion) was observed in 11 among 63 patients with definite NVIE and no patients with rejected IE (sensitivity 18%, specificity 100%). Among the 63 patients with a final diagnosis of NVE, a peripheral embolism or mycotic aneurysm was observed in 20 cases (32%). Considering this, the ESC 2015 classification increased the sensitivity of Duke criteria from 64 to 70% ( P < 0.001) without any change on specificity ( P < 0.001). Twenty-four patients (38%) were diagnosed with secondary infectious sites or infectious portal of entry. A diffuse splenic uptake was observed in 39 (52%) patients, including 37 (59%) of patients with a final diagnosis of NVE (specificity 83%). 1. The value of 18 F-FDG PET/CT in NVE diagnosis is poor 2. Usefulness of PET/CT remains high when concerning embolic or neoplastic detection. 3. Our study describes for the first time in NVE a new potential endocarditis criterion, i.e. the presence of a diffuse splenic uptake on PET/CT.