Introduction: Although oral P2Y12 inhibitors (P2Y12-Is) are one of the most commonly prescribed medication classes in patients with end stage kidney disease on dialysis (ESKD), scarce data exist regarding their benefits and risks. Methods: We compared effectiveness and safety of clopidogrel, prasugrel, and ticagrelor in a longitudinal study using the United States Renal Data System registry of Medicare beneficiaries with ESKD. Individuals who filled new P2Y12-I prescriptions between 2011 and 2015 were included and followed until death or censoring. The primary exposure variable was P2Y12-I assignment. The primary outcome variable was death. Secondary outcomes included cardiovascular (CV) death, coronary revascularization, and gastrointestinal (GI) hemorrhage. Survival analyses were performed after propensity matching. Results: Of 44,619 patients with ESKD who received P2Y12-Is, 95% received clopidogrel (n = 42,523), 3% prasugrel (n = 1205), and 2% ticagrelor (n = 891). To balance baseline differences, propensity-matching was performed: 1:6 for prasugrel (n = 1189) versus clopidogrel (n = 7134); 1:4 for ticagrelor (n = 880) versus clopidogrel (n = 3520); and 1:1 for ticagrelor versus prasugrel (n = 880). Prasugrel was associated with a reduced risk for death versus clopidogrel and ticagrelor (adjusted hazard ratio [HR] = 0.82; 95% CI: 0.73–0.93 and 0.78; 95% CI: 0.64–0.95). Compared with clopidogrel, prasugrel reduced risk for coronary revascularization (HR = 0.91; 95% CI: 0.86–0.96). There were no differences in GI hemorrhage between P2Y12-Is. Conclusion: In patients with ESKD, prasugrel compared with others reduced risk of death possibly by reducing risk for coronary revascularizations and without worsening gastrointestinal hemorrhage. Future trials are imperative to compare efficacy and safety of P2Y12-Is in patients with ESKD.