Low-dose aspirin has been postulated to decrease risks of cardiovascular disease by affecting atherosclerotic progression as well as acute thrombosis. In the Physicians' Health Study, a randomized double-blind placebo-controlled trial of alternate day aspirin (325 mg), 22,071 apparently healthy male physicians were treated and followed over a period of 5 years for the occurrence of myocardial infarction and of new angina pectoris. In an analysis of the cumulative incidence and cumulative relative risks of these end points, it was found that the full protective effect of aspirin in reducing the risk of myocardial infarction is apparent soon after initiation of therapy and does not change over time. In contrast, long-term aspirin therapy has no apparent role in decreasing the risk of developing future angina pectoris. Taken together, these clinical observations support the hypothesis that the primary effect of prophylactic low-dose aspirin therapy is to inhibit acute thrombosis, but do not support the hypothesis that long-term platelet inhibition for a duration of up to 5 years slows the initiation and progression of atherosclerosis.