Background We investigated the clinical features, microbiology, and short- and long-term outcomes of incident infective endocarditis (IE) hospitalizations in patients with end-stage kidney disease (ESKD) requiring dialysis or with a kidney transplant over 25 years in Scotland. Methods and Results In this retrospective, population-based cohort study linking national hospitalization and mortality data, we identified patients with a history of ESKD and hospitalized with IE in Scotland between January 1, 1990 and December 31, 2014. From January 1, 2008, individual IE hospitalizations were additionally linked to national microbiology data. Multivariable logistic regression, adjusting for patient demographics and comorbidities, evaluated the association between ESKD and all-cause death at 1 and 3 years. Of 7638 incident IE hospitalizations between 1990 and 2014, 2.8% (216/7638) occurred in 210 patients with ESKD and 97.2% (7422/7638) occurred in 7303 patients without ESKD. Positive findings from blood cultures were identified in 42% (950/2267) of incident IE hospitalizations from 2008. Staphylococcus aureus was isolated in 25.9% (21/81) and 12.8% (280/2186) of patients with and without ESKD, respectively (P=0.002). ESKD was associated with an increased odds of death at 1 (44.9% versus 31.4%; adjusted odds ratio [aOR], 2.47, 95% CI, 1.85-3.30;, P<0.001) and 3 years (63.9% versus 42.8%; aOR, 3.77; 95% CI, 2.79-5.12; P<0.001). Conclusions IE is associated with a poor prognosis in patients with ESKD, especially in the longer term. Compared with patients without ESKD, patients with ESKD were twice as likely to die within 1 year, and 3 times as likely to die within 3 years of IE hospitalization.