The interrelationships among sex hormones, caloric intake, and intermediary metabolism in health and disease are uncertain. Studies in malnourished patients with AIDS and cancer show that megestrol acetate (MA) therapy increases appetite, body weight, and body fat, while it decreases serum testosterone (T) concentration. In this study, the separate and combined effects of MA and T were investigated in 65 young adult, male, castrated, Sprague-Dawley rats who received subcutaneous implants containing placebo, MA, T, or both MA and T for 11 wk. By hierarchical multiple regression analysis, MA therapy decreased weight gain and food intake (P < 0.01), increased body fat (P = 0.024), decreased body protein (P < 0.001), and decreased the portion of calories accrued as protein rather than fat (P ratio, P < 0.03). T alone decreased fat (P < 0.03), but had no significant effect on food intake, the relative number of consumed calories utilized for growth (food efficiency), body weight, or protein. The interaction of MA and T did not affect food intake or food efficiency, but increased body weight (P < 0.02), protein (P < 0.05) and the P ratio (P < 0.02). The portion of weight gain as fat was reduced from 47.3% with MA alone to 27.4% when MA and T were combined. Thus, megestrol acetate has significant antianabolic effects that are independent of its effects upon food intake. The addition of testosterone to megestrol acetate partially antagonized MA's inhibition of lean mass accretion in these rats.