Objectives. We sought to assess the role of aspirin in a precisely defined cohort with coronary disease receiving current therapy. Background. Prior results suggest that aspirin modestly decreases cardiac mortality in patients with coronary disease. However, these findings reflect heterogeneous study conditions and earlier management strategies. Methods. We utilized findings from the Multicenter Study of Myocardial Ischemia, which enrolled 936 subjects 1 to 6 months after an acute myocardial infarction (n = 651 [70%]) or unstable angina (n = 285 [30%]). The follow- up period averaged 23 months, with treatment determined by referring physicians. Results. At enrollment, 751 patients (80%) took aspirin regularly, usually 250 to 325 mg/day. Before enrollment, 291 patients (31%) had thrombolysis, and 352 (38%) had coronary angioplasty. During follow-up, cardiac death occurred in 22 patients, all-cause mortality in 31 and cardiac death or nonfatal myocardial infarction in 70. Each of these outcomes was significantly less frequent among aspirin users. Cardiac death rate was markedly reduced: 1.6% for aspirin users and 5.4% for nonusers (p = 0.005). These differences were not explained by imbalances in predictors of postinfarction risk or therapy other than aspirin (Cox hazard ratio 0.37, p = 0.023). They persisted at least 2 years after enrollment. The difference in mortality rate was particularly prominent after thrombolysis: 0.9% for aspirin users and 8.8% for nonusers (p = 0.004). Conclusions. Reduction in cardiac deaths among aspirin users is substantially greater than that reported previously. Although derived secondarily, our findings suggest that current practice leads to situations in which aspirin exerts a long-term, life-protecting action, particularly after thrombolysis.