Patients with diabetes mellitus (DM) have a higher incidence of infections, and those with bacteremia are more prone to develop sepsis and infective endocarditis (IE). Nevertheless, data concerning the impact of DM on the prognosis of patients with IE are limited and sometimes contradictory. We examined the impact of DM on the inhospital outcome of left-sided IE in a large cohort of patients. We studied 594 consecutive episodes of left-sided IE diagnosed at 3 tertiary care centers. They were divided into 2 groups: episodes in patients with DM (n = 114) and episodes in patients without DM (n = 480). We retrospectively analyzed the influence of DM therapy on patient outcome. Compared to patients without DM, patients with DM were older (67 ± 10 vs. 60 ± 15 yr; p < 0.001), less frequently male (53.5% vs. 67.9%; p = 0.004), and more commonly had chronic renal failure (23.9% vs. 6.9%; p < 0.001) and chronic obstructive pulmonary disease (14.6% vs. 7.8%; p = 0.019). Enterococcus (14.9% vs. 7.4%; p = 0.011) and Streptococcus bovis (8.8% vs. 3.8%; p = 0.024) were isolated more frequently. In the univariable analysis, septic shock (29.2% vs. 16.4%; p = 0.005) and mortality (43.5% vs. 30.0%; p = 0.008) were more common among patients with DM than in those without. Considering the different treatments for DM, septic shock (33.3%; p = 0.011) and death (50.8%; p = 0.012) were more frequent in patients receiving oral medication to treat diabetes than in patients with the other treatment modalities. However, multivariable analysis showed that DM had an independent association with development of septic shock (OR 2.282; 95% CI 1.186-4.393), but it was not a predictor of inhospital mortality.Staphylococci were the most frequently involved microorganisms in all patients; however, Enterococcus and Streptococcus bovis were more frequently isolated from individuals with DM and left-sided IE, whereas viridans group streptococci were more commonly isolated from those with left-sided IE who did not have DM. DM was independently associated with the development of septic shock, but it was not an independent predictor of inhospital mortality in patients with left-sided IE.