Background: Infective endocarditis (IE) is a common and serious complication in patients receiving chronic hemodialysis (HD). Objectives: This study sought to investigate whether there are significant differences in complications, cardiac surgery, relapses, and mortality between IE cases in HD and non-HD patients. Methods: Prospective cohort study (International Collaboration on Endocarditis databases, encompassing 7,715 IE episodes from 2000 to 2006 and from 2008 to 2012). Descriptive analysis of baseline characteristics, epidemiological and etiological features, complications and outcomes, and their comparison between HD and non-HD patients was performed. Risk factors for major embolic events, cardiac surgery, relapses, and in-hospital and 6-month mortality were investigated in HD-patients using multivariable logistic regression. Results: A total of 6,691 patients were included and 553 (8.3%) received HD. North America had a higher HD-IE proportion than the other regions. The predominant microorganism was Staphylococcus aureus (47.8%), followed by enterococci (15.4%). Both in-hospital and 6-month mortality were significantly higher in HD versus non-HD-IE patients (30.4% vs. 17% and 39.8% vs. 20.7%, respectively; p < 0.001). Cardiac surgery was less frequently performed among HD patients (30.6% vs. 46.2%; p < 0.001), whereas relapses were higher (9.4% vs. 2.7%; p < 0.001). Risk factors for 6-month mortality included Charlson score (hazard ratio [HR]: 1.26; 95% confidence interval [CI]: 1.11 to 1.44; p = 0.001), CNS emboli and other emboli (HR: 3.11; 95% CI: 1.84 to 5.27; p < 0.001; and HR: 1.73; 95% CI: 1.02 to 2.93; p = 0.04, respectively), persistent bacteremia (HR: 1.79; 95% CI: 1.11 to 2.88; p = 0.02), and acute onset heart failure (HR: 2.37; 95% CI: 1.49 to 3.78; p < 0.001). Conclusions: HD-IE is a health care-associated infection chiefly caused by S. aureus, with increasing rates of enterococcal IE. Mortality and relapses are very high and significantly larger than in non-HD-IE patients, whereas cardiac surgery is less frequently performed.