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Background: To evaluate the prognostic impact of diabetes mellitus (DM) in patients with Infective Endocarditis (IE)., Methods and Results: 375 patients with diagnosis of IE referred to our Hospital between 1994-2017 were retrospectively included; diabetes was reported in 129 (34.4%). Diabetic patients were older than non-diabetic (66±1 vs. 57±2 years, p<0.001) and showed a higher prevalence of comorbidities such as hypertension (75 vs. 54%, p<0.001), coronary artery disease (30 vs. 12%, p<0.001) and history of heart failure (HF; 24 vs. 13%, p = 0.021). Echocardiography showed a higher incidence of paravalvular complications (82 vs. 64%, p<0.001) and a lower left ventricular ejection fraction (LVEF; 52±11 vs. 55±10%, p = 0.001) in diabetic than in non-diabetic patients. In-hospital mortality was higher in diabetic patients (83 vs. 74%; p = 0.030). At logistic regression, history of HF (OR = 3.1, 95%CI: 1.87-5.29, p<0.001) resulted an independent predictor of in-hospital death. At long-term follow-up [median 24(7-84) months], the Kaplan-Meier analysis showed a significantly lower survival free from all-cause death in the group with diabetes (Log-rank<0.001). At the propensity score adjusted Cox multivariable analysis, DM (HR = 1.76, 95%CI: 1.18-2.6, p = 0.005), age (HR = 1.03, 95%CI: 1.02-1.05, p<0.001), intravenous drug users (HR = 5.42, 95%CI: 2.55-11.51, p<0.001) and low LVEF (HR = 0.98, 95%CI: 0.96-0.99, p = 0.013) were independently associated to a higher mortality., Conclusion: In patients with IE, DM is associated to a higher prevalence of anatomic complications and a more impaired LVEF. Diabetic patients show a significantly lower survival both in hospital and during follow-up compared to the non-diabetic ones., Competing Interests: The authors have declared that no competing interests exist.