AbstractThe 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 pri