The oxidative stress induced by high glucose concentration contributes to tissue damage associated with diabetes, including renal injury. Dehydroepiandrosterone (DHEA), the major secretory product of the human adrenal gland, has been shown to possess a multi-targeted antioxidant activity which is also effective against lipid peroxidation induced by high glucose. In this study we evaluated the effect of DHEA on the growth impairment which high glucose concentration induces in cultured rat mesangial cells. Primary cultures of rat mesangial cells were grown for 10 days in media containing either normal (i.e. 5.6 mmol/l) or high (i.e. 30 mmol/l) concentrations of glucose, without or with DHEA at different concentrations. The impairment of cell growth induced by high glucose was reversed by 100 nmol/l and 500 nmol/l DHEA, which had no effect on mesangial cells cultured in media containing glucose at the normal physiological concentration (5.6 mmol/l). In high-glucose cultured mesangial cells, DHEA also attenuated the lipid peroxidation, as measured by thiobarbituric acid reactive substances (TBARS) generation and 4-hydroxynonenal (HNE) concentration, and preserved the cellular content of reduced glutathione as well as the membrane Na+/K+ ATPase activity. The data further support the protective effect of DHEA against oxidative damage induced by high glucose concentrations, and bring into focus its possible effectiveness in preventing chronic complications of diabetes.