Background and objectives: Few studies have examined risk factors for hemorrhage in hemodialysis patients. The contribution of warfarin and antiplatelet agent exposure to the incidence of first major bleeding episodes in hemodialysis patients was determined.Design, setting, participants, & measurements: Retrospective chart review was performed in eligible hemodialysis patients. Incidence rates were determined as the number of first major bleeding events divided by the total exposure time on each treatment combination. Time-dependent covariates and Cox proportional hazard models were used to determine the hazard rate of having a first major bleeding event.Results: A total of 1028 person-years of exposure were observed from 255 patients with a median follow-up time of 3.6 yr. The incidence rate of major bleeding episodes was 2.5% per person-year. The incidence of major bleeding episodes was 3.1% per person-year of warfarin exposure, 4.4% per person-year of aspirin exposure, and 6.3% per person-year of exposure to the combination of warfarin and aspirin. Compared with patients who were not prescribed warfarin or aspirin, the multivariable hazard ratio for time to first major bleeding event was 3.59 for warfarin, 5.24 for aspirin, and 6.19 for the combination of aspirin and warfarin.Conclusions: The risk for major bleeding episodes in hemodialysis patients increases significantly while on aspirin and/or warfarin, although warfarin alone did not reach statistical significance. Future studies should evaluate the efficacy of these agents in the secondary prevention of cardiovascular events in this high-risk population.