The purpose of this investigation was to study the influence of diabetes mellitus (DM) on outcomes of infective endocarditis (IE). Outcomes were compared between 150 diabetic and 905 non-diabetic patients with IE from the International Collaboration on Endocarditis Merged Database. Compared to non-diabetic patients, diabetic patients were older (median age 63 vs 57 y, p<0.001), were more often female (42.0% vs 31.9%, p=0.01), more often had comorbidities (41.5% vs 26.7%, p<0.001), and were more likely to be dialysis dependent (12.7% vs 4.0%, p<0.001). S. aureus was isolated more often (30.7% vs 21.7%, p=0.02), and microorganisms from the viridans Streptococcus group less often (16.7% vs 28.2%, p = 0.001) in the diabetic group. There was no difference with respect to the presence of congestive heart failure, embolism, intra-cardiac abscess, new valvular regurgitation, or valvular vegetation. Diabetic patients underwent surgical intervention less frequently (32.0% vs 44.9%, p = 0.003), and had higher overall in-hospital mortality (30.3% vs 18.6%, p = 0.001). On multivariable analysis, DM was an independent predictor of mortality (odds ratio (OR) = 1.71, 95% confidence interval (CI) 1.08-2.70), especially in male patients, as diabetic males had higher mortality than non-diabetic males (OR 2.18, CI 1.08-4.35). DM is an independent predictor of in-hospital mortality among patients hospitalized with IE.