The purpose of this study was to examine the effects of aspirin use on mortality and morbidity rates in a subset of the control group of the Program on the Surgical Control of the Hyperlipidemias (POSCH) that was stratified by cigarette smoking status at the time of randomization. The clinical impact of aspirin intake in cigarette smokers and former cigarette smokers has not been well studied. POSCH was a randomized, controlled, clinical trial designed to ascertain the effects of lipid modification by the partial ileal bypass operation on clinical end-points and arteriographic changes in postmyocardial infarction subjects with hypercholesterolemia. Cohorts of cigarette smokers in the diet-control group were evaluated for overall and atherosclerotic coronary heart disease (ACHD) mortality rates and recurrent confirmed nofatal myocardial infarction rates. In current cigarette smokers at baseline (n = 90) with a mean follow-up of 8.3 years, the overall mortality rate was 45.2% in patients with no aspirin use and 10.4% in patients who reported even infrequent aspirin use (relative risk = 4.3, 95% confidence interval (CI) = 2.4 to 10.6, p < 0.001). For ACHD mortality in this cohort, the relative risk was 17.1 (35.7% vs 2.1%, 95% CI = 1.4 to 125.0, p < 0.001); for the combined end-point of ACHD mortality and nonfatal myocardial infarction, the relative risk was 2.4 (40.5% vs 16.7%, 95% CI = 1.25 to 5.1, p = 0.018). In former cigarette smokers with no aspirin use at baseline (n = 92) with a mean follow-up of 8.8 years, the relative risk of overall mortality was 3.1 (20.0% vs 6.5%, 95% CI = 1.0 to 10.2, p = 0.07), ACHD mortality, 3.4 (167.% vs 4.8%, 95% CI = 0.9 to 13.5, p = 0.11); and combined ACHD mortality and confirmed nonfatal myocardial infarction, 1.1 (23.3% vs 21.0%, 95% CI = 0.5 to 2.5, p = 0.79). After adjustment for age, gender, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, Quetelet index, ejection fraction, extent of coronary disease at baseline, and length of follow-up, none of these relative risks changed appreciably. The risk of overall mortality, aCHD mortality, and combined ACHD mortality and recurrent confirmed nonfatal myocardial infarction may be significantly reduced by aspirin use in post-myocardial infarction cigarette smokers. However, the subjects included in this analysis were highly selected and may not be totally representative of postmyocardial infarction patients. Nonetheless, when extensive counseling regarding the negative consequences of continued cigarette smoking fails to cause smoking cessation in postmyocardial infarction patients, it may be exceedingly prudent to recommended aspirin usage.