Background. Infective Endocarditis (IE) is a severe condition. Diabetes mellitus (DM) has been associated with a poor prognosis in other settings. Our aim was to describe the profile and prognosis of IE with and without DM and to analyze the prognostic relevance of DM-related organ damage. Methods. Retrospective analysis of the Spanish IE Registry (2008–2020). Results. The cohort comprises 5590 IE patients with a mean age of 65.0 ± 15.5 years; 3764 (67.3%) were male. DM was found in 1625 patients (29.1%) and 515 presented DM-related organ damage. DM prevalence during the first half of the study period was 27.6% vs. 30.6% in the last half, p = 0.015. Patients with DM presented higher in-hospital mortality than those without DM (521 [32.1%] vs. 924 [23.3%], p < 0.001) and higher one-year mortality (640 [39.4%] vs. 1131 [28.5%], p < 0.001). Among DM patients, organ damage was associated with higher in-hospital (200 [38.8%] vs. 321 [28.9%], p < 0.001) and one-year mortality (247 [48.0%] vs. 393 [35.4%], p < 0.001). Multivariate analyses showed an independent association of DM with in-hospital (odds ratio [OR] = 1.34, 95% confidence interval [CI]: 1.16–1.55, p < 0.001) and one-year mortality (OR = 1.38, 95% CI: 1.21–1.59, p < 0.001). Among DM patients, organ damage was independently associated with higher in-hospital (OR = 1.37, 95% CI: 1.06–1.76, p = 0.015) and one-year mortality (OR = 1.59, 95% CI = 1.26–2.01, p < 0.001) Conclusions. The prevalence of DM among patients with IE is increasing and is already above 30%. DM is independently associated with a poor prognosis, particularly in the case of DM with organ damage.