The Physicians' Health Study is a randomized, placebo-controlled, double-blind clinical trial underway in the United States to assess the effects of aspirin (325 mg q.o.d.) on total cardiovascular mortality, and of beta-carotene (50 mg q.o.d.) on cancer incidence. The participants are 22,071 U.S. male physicians between the ages of 40-84 years. The design of the study is 2 x 2 factorial, which enables us to address two important research questions simultaneously. The trial is conducted entirely by mail, which involves sending calendar packs of drugs and questionnaires on health status and compliance, initially at six-month then at annual intervals. Compliance and follow-up rates to date are excellent. The large size of the trial, its simple design, and the use of highly motivated, dedicated, and health-conscious physicians should allow us to perform definitive tests of whether low-dose aspirin consumption reduces total cardiovascular mortality and beta-carotene decreases cancer incidence in a healthy population.