Increased cardiovascular morbidity and mortality among cigarette smokers may be mediated in part by enhanced platelet function. Previous data showed that cigarette smoking--induced lowering of the platelet aggregate ratio of normal individuals was prevented by taking aspirin before smoking. Our study was undertaken to determine whether similar results would occur in men with coronary artery disease and whether platelet factor 4 would be released. A random-order, double-blind crossover study comparing the effects of placebo, 0.15 gm aspirin, and 0.30 gm aspirin was done in 30 male habitual smokers with coronary artery disease. Each man took a tablet containing placebo or aspirin and then abstained from smoking for 12 hours before each of three 20-minute periods of smoking two tobacco cigarettes. Immediately before and after smoking, the platelet aggregate ratio and the concentration of platelet factor 4 in platelet-poor plasma were determined from antecubital venous blood. Twelve hours after placebo, the geometric mean concentration of platelet factor 4 was 13.6 ng/ml before and 19.7 ng/ml after smoking (P = 0.0006). The mean platelet aggregate ratio was 0.77 and 0.72, respectively (P less than 0.00001). Neither dose of aspirin affected the presmoking value of or the smoking-induced change in either variable. The data indicate that smoking stimulated platelet aggregate formation and release of the contents of platelet alpha-granules, which were unaffected by preadministration of aspirin. This contrasts with the previous study of normal habitual smokers whose ingestion of 0.32 gm aspirin prevented a smoking-induced decrease in the platelet aggregate ratio.