Total direct costs of the Women's Health Trial (WHT), a large multicenter prevention trial, were reduced by more than 50% by means of research cost analysis conducted during the trial design phase. The unit costs of specific trial activities were estimated so that total direct costs of the trial could be predicted from design parameters. The relative costs of screening, treatment, and follow-up, and the fixed costs associated with each clinical center in a multicenter prevention trial were taken into account. Direct costs of the WHT were reduced from +195 million to +95 million by refinement of the trial protocol, selection of an efficient design, and consideration of trial logistics. The analyses suggest several ways to reduce costs in a prevention trial. Use of the case-cohort approach can reduce costs substantially when the protocol includes collection of specimens or data that are costly to process. When establishing and maintaining a clinical center represents a significant proportion of a clinical center's costs, use of a smaller number of larger clinical centers offers important cost savings. Because restrictive eligibility requirements reduce the recruitment potential of each clinical center, use of high-risk participants may not improve the efficiency of a prevention trial; its favorable impact on sample size may fail to compensate for its cost in terms of additional clinical centers and higher recruitment costs.