Selenium and vitamin E are probably 2 of the most popular dietary supplements considered for use in the reduction of prostate cancer risk. This enthusiasm is reflected in the initiation of the Selenium and Vitamin E Chemoprevention Trial (SELECT). Is there sufficient evidence to support the use of these supplements in a large-scale prospective trial for patients who want to reduce the risk of prostate cancer? Results from numerous laboratory and observational studies support the use of these supplements, and data from recent prospective trials also add partial support. However, a closer analysis of the data reveals some interesting and unique associations. Selenium supplements provided a benefit only for those individuals who had lower levels of baseline plasma selenium. Other subjects, with normal or higher levels, did not benefit and may have an increased risk for prostate cancer. The concept that supplements reduce prostate cancer risk only in those at a higher risk and/or those with lower plasma levels of these compounds is supported by trials examining beta-carotene supplements. Smokers may be the only individuals who benefit, as has also been shown with vitamin E supplementation. In 4 recent prospective studies, vitamin E was found to reduce the risk of prostate cancer in past/recent and current smokers and those with low levels of this vitamin. Vitamin E supplements in higher doses (> or =100 IU) were also associated with a higher risk of aggressive or fatal prostate cancer in nonsmokers from a past prospective study. The dose of vitamin E in the SELECT trial (400 IU/day) is 8 times higher than what has been suggested to be effective (50 IU/day) by the largest randomized prospective trial in which the incidence rate of prostate cancer was used as an endpoint. Recent research also suggests that dietary vitamin E may be associated with a lower risk of prostate cancer than the vitamin E supplement. Additionally, recent results from all past cardiovascular prospective, randomized trials suggest that vitamin E shows little benefit for cardiovascular disease risk, especially at the dose being used in the SELECT trial. Other intriguing positive findings from past prospective studies of supplements suggest that aspirin and other nonsteroidal anti-inflammatory drugs have a role in reducing the risk of prostate cancer or other types of cancer (eg, colon cancer). It may be time to conduct a large costly trial to reconsider the use of selenium and vitamin E supplements for the reduction of prostate cancer risk. Some evidence for the use of these supplements exists, but serious embellishment of study findings may be leading to an inappropriate use of these supplements in a clinical setting.