The U.S. Physicians' Health Study, a primary prevention trial of low-dose aspirin in the reduction of cardiovascular disease and of beta-carotene in lowering cancer risk, implemented a number of design strategies to decrease costs and increase efficiency. These included the choice of physicians as the study population, use of a factorial design, implementation of a pre-randomization run-in phase, and the collection of pre-randomization blood specimens. The use of these strategies enabled us to enroll 22,071 subjects and maintain high compliance and long-term follow-up at a fraction of the usual cost of large-scale trials of primary prevention.