The effects of either dehydroepiandrosterone (DHEA) or clofibric acid (CFA) treatment on obese female Zucker rats were compared. After 5 wk of treatment, food intake, body weight gain and food efficiency ratio of DHEA-treated rats were 85, 64 and 75%, respectively, of those of CFA-treated and control rats. Liver weights of DHEA- and CFA-treated rats were higher than those of control rats. Non-fasting serum glucose levels were similar in all groups, but serum insulin level of DHEA-treated rats was 59% of that in CFA-treated and control rats. Results of glucose tolerance tests were not different among the groups. Mitochondrial state 3 and 4 rates expressed per g liver or per liver with either glutamate-malate or succinate as substrate were higher in DHEA-treated rats than in CFA-treated or control rats. Mitochondrial long-chain fatty acyl-CoA hydrolase activity was 8.5 and 4 times higher in DHEA- and CFA-treated rats, respectively, than in control rats. These results suggest that although DHEA and CFA affect some hepatic biochemical parameters similarly, they are distinct in their effects on body weight, serum insulin and mitochondrial respiration in obese Zucker rats.