A multicenter randomized trial comparing megestrol acetate 120 mg/d, plus diethylstilbestrol (DES) 0.1 to 3 mg/d in patients with stage D2 prostate cancer was undertaken to compare the efficacy and toxicity of these two regimens. Pretreatment characteristics, including pathologic grade, performance status, age, and disease-related symptoms were similar in the two groups. Of 81 patients who have been entered in the study, 77 are evaluable for response and toxicity at a mean follow-up of 13.3 months. Using National Prostate Cancer Project (NPCP) criteria, no difference in response rate is noted (73% v 76%) or in disease-free survival and overall survival. The ability to suppress serum testosterone to castration levels and to maintain this suppression is equivalent in both treatment groups. However, treatment-related toxicity, including edema, hypertension, and gynecomastia, occurred at a significantly greater frequency, severity, and after a shorter treatment period in the DES-treated group. No difference in major cardiovascular events was noted. Since megestrol acetate plus minidose DES is equivalent to DES in achieving treatment responses in patients with carcinoma of the prostate, it is a preferable treatment because of its improved side-effect profile.