It was reported recently that 4 weeks of dehydroepiandrosterone (DHEA) treatment [5.55 mmol/day (1600 mg/day), orally] reduced body fat and increased lean body mass in healthy men. The present study was performed to examine whether these effects could be explained by increased energy expenditure and muscle protein synthesis. Eight healthy men were given placebo and DHEA (1600 mg/day) for 4 weeks each in a double blind cross-over study. DHEA treatment caused a 9-fold increase in mean plasma DHEA sulfate concentrations, but had no significant effect on body weight or on two indices of lean body mass (total body water and total body potassium). DHEA had no effect on any of the parameters of energy and protein metabolism, including resting metabolic rate, total energy expenditure (estimated by the 2H2(18)O method during the final 2 weeks of each treatment period), leucine flux (an index of whole body proteolysis), the nonoxidized portion of leucine flux (an index of whole body protein synthesis), and the rate of incorporation of leucine into muscle protein. Circulating levels of cholesterol, T3, and T4 also were unaffected by DHEA. These data suggest that DHEA is not an important regulator of energy or protein metabolism in humans.