Dehydroepiandrosterone (DHEA) lowers serum cholesterol, particularly the low density lipoprotein (LDL) fraction, in rhesus monkeys on a commercial diet (12% calories from fat, 0.0083% cholesterol). We fed rhesus monkeys a diet of 30% calories from fat and 0.1% cholesterol for 12 weeks, then commercial chow for 7 weeks. Six monkeys each received DHEA or placebo, orally for 17 weeks. Food intake increased the first 6 weeks, but decreased thereafter. Monkeys had a 22% mean weight gain while on high fat diet. DHEA monkeys had higher T4 levels than placebo monkeys at weeks 8 and 16. After 12 weeks on high fat diet, all monkeys had elevated serum cholesterol concentrations, an increase in amount and percentage of intermediate density lipoprotein and LDL cholesterol, and an increase in amount, but a decrease in percentage of high density lipoprotein cholesterol. There were no significant differences in serum cholesterol or plasma lipoprotein concentrations between DHEA and placebo monkeys while on high fat diet (a trend toward lower levels was noted in the DHEA group). On commercial chow, plasma lipoprotein concentrations decreased for all monkeys, and DHEA monkeys had significantly lower total and LDL cholesterol than placebo monkeys. We conclude that a high fat diet (30% fat) masks any cholesterol-lowering effects of DHEA.