This application proposes to analyze existing data from the Physicians Health Study (PHS), a randomized primary prevention trial of low-dose aspirin and beta carotene conducted among 22,071 U.S. male physicians, to address questions concerning aspirin and cardiovascular (CV) disease that could not adequately be addressed during the randomized aspirin period. The aspirin component of the trial was terminated on January 25, 1988, due to a demonstrated benefit of aspirin on myocardial infarction. At that time, however, the number of strokes and CV deaths experienced by trial participants was inadequate to definitively evaluate these endpoints. The beta carotene component of the trial continued uninterrupted until its scheduled termination in December, 1996. During this period detailed information continued to be collected on post-trial aspirin use through annual questionnaires. As of October, 1995, the number of deaths, including cardiovascular deaths, had increased fourfold from that in the randomized period, and the number of strokes had increased 3.5 times. We thus propose to use data from both the randomized aspirin period and the observational period following the trial to assess the impact of aspirin use on cardiovascular and total mortality, and the long-term impact of aspirin use on subsequent stroke and MI. The proposed methods will include analyses of both randomized aspirin assignment and of time-varying aspirin use, as assessed on the annual questionnaires. Because of the potential for bias, the propensity for aspirin use, particularly during the observational period must be taken into account. Analyses will include use of proportional hazards models allowing for both time-varying effects of aspirin use and controlling for time-varying confounders, as well as more complex procedures using causal modeling.