Previous studies showed that administration of dehydroepiandrosterone (DHEA) to lean and genetically obese Zucker rats reduced body weight. In the present experiments, the effect of DHEA treatment in rats with diet-induced obesity was evaluated. In experiment 1, male Sprague-Dawley rats (300 g) were fed a nonpurified diet (reference group) or a condensed milk-corn oil nonpurified diet [diet-induced obese (DIO) rats] for 7 wk. Then, 0.6% DHEA was included in the food of one-half of the DIO rats (DIO + DHEA rats). After 6 wk, DIO rats weighed 23% more and had greater fat pad weights, cell size and cell number than reference and DIO + DHEA rats. Brown fat mitochondrial respiration was similar in all groups. DIO rats had higher serum cholesterol and triacylglycerol concentrations than reference and DIO + DHEA rats. DIO + DHEA rats had lower serum insulin levels than DIO and reference rats. In experiment 2, male Sprague-Dawley rats (460 g) were fed either the nonpurified diet or the condensed milk diet for 8 wk. Condensed milk-fed rats were then divided into DIO and diet-resistant groups. One-half of the rats in each group were fed 0.6% DHEA for 2 wk. Body weights and serum glucose, insulin, triacylglycerol and triiodothyronine levels were lowered by DHEA treatment in all groups. Liver mitochondrial state 3 respiration rates per gram and per liver and peroxisomal beta-oxidation were higher in DHEA-treated than in control rats. In DIO rats, DHEA treatment appears to interfere with hyperplastic adipose tissue growth. In this strain of rats, DHEA appears to have hypolipidemic and hypoinsulinemic effects.