The plasma levels of dehydroepiandrosterone and its sulfated form decline ~80% between ages 25 and 75 yrs. Muscle mass and strength also decrease with aging. Published data on the effects of DHEA replacement on muscle mass and strength are conflicting. The goals of this study were to determine whether DHEA replacement increases muscle mass and strength, and/or enhances the effects of heavy resistance exercise in elderly women and men. We conducted a randomized, double blind, placebo-controlled study of the effects of 10 mo of DHEA replacement therapy with the addition of weight-lifting exercise training during the last 4 mo of the study (DHEA + Exercise group, n=29; Placebo + Exercise group, n=27). DHEA alone for 6 mo did not significantly increase strength or thigh muscle volume. No significant increases in strength or thigh muscle volume occurred in response to 6 mo of DHEA replacement. However, DHEA therapy potentiated the effect of 4 months of weight-lifting training on muscle strength evaluated by means of one repetition maximum measurement and by Cybex dynamometry, and on thigh muscle volume measured by magnetic resonance imaging. Serum insulin-like growth factor concentration increased in response to DHEA replacement. This study provides evidence that DHEA replacement has the beneficial effect of enhancing the increases in muscle mass and strength induced by heavy resistance exercise in elderly individuals.