Preclinical, epidemiological, and phase III data from randomized, placebo-controlled clinical trials suggest that both selenium and vitamin E have potential efficacy in prostate cancer prevention. In vitro evidence suggests that selenium and vitamin E work synergistically to cause cell-cycle arrest, induce caspase-mediated apoptosis, and act as antiandrogens in arresting clonal expansion of nascent tumors. The Selenium and Vitamin E Cancer Prevention Trial (SELECT), sponsored by the National Cancer Institute, is an intergroup Phase III, randomized, double-blind, placebo-controlled, population-based clinical trial designed to test the efficacy of selenium and vitamin E alone and in combination in the prevention of prostate cancer. The study has a 2 x 2 factorial design with a target accrual of 32,400. Eligibility criteria include an age of at least 50 years for African Americans and of at least 55 years for Caucasians; a DRE not suspicious for cancer; a serum PSA no greater than 4 ng/mL; and a normal blood pressure. Randomization will be equally distributed among the four study arms, with intervention consisting of a daily oral dose of study supplement (200 mug l-selenomethionine or 400 mg of racemic alpha-tocopheryl) or matched placebo. Study duration is planned for 12 years, with a 5-year uniform accrual period and a minimum of 7 and maximum of 12 years of intervention. The primary endpoint for SELECT is the clinical incidence of prostate cancer as determined by a recommended routine clinical diagnostic work-up, including yearly DRE and serum PSA level. SELECT is the second large-scale study of chemoprevention for prostate cancer. Enrollment began in 2001, with final results anticipated in 2013.