Abstract Background We performed a study to assess sex-differences in incidence (2016–2020), clinical characteristics, use of therapeutic procedures, and in-hospital outcomes in patients with infective endocarditis (IE) according to T2DM status. Methods Ours was a retrospective cohort study using data from the Spanish National Hospital Discharge Database. We estimated the incidence of hospitalizations for IE in men and women aged ≥ 40 years with and without T2DM. Propensity score matching (PSM) and multivariable logistic regression were used to compare subgroups according to sex and the presence of T2DM. Results From 2016 to 2020, IE was coded in 9,958 patients (66.79% men). T2DM was diagnosed in 2,668 (26.79%). The incidence of IE increased significantly from 15.29 cases per 100,000 persons with T2DM in 2016 to 17.69 in 2020 (p < 0.001). However, this increment was significant only among men with T2DM (19.47 cases per 100,000 in 2016 vs. 22.84 in 2020; p = 0.003). The age-adjusted incidence of IE was significantly higher in people with T2DM (both sexes) than in those without T2DM (IRR, 2.86; 95% CI, 2.74–2.99). The incidence of IE was higher in men with T2DM than in women with T2DM (adjusted IRR, 1.85; 95% CI, 1.54–3.31). After PSM, in-hospital mortality (IHM) was higher among T2DM women than matched T2DM men (22.65% vs. 18.0%; p = 0.018). The presence of T2DM was not associated with IHM in men or women. Conclusions T2DM is associated with a higher incidence of hospitalization for IE. Findings for T2DM patients who had experienced IE differed by sex, with higher incidence rates and lower IHM in men than in women. T2DM was not associated to IHM in IE in men or in women.