The effectiveness of combination therapy with diethylstilbestrol, cyclophosphamide, and 5-fluorouracil (DES + CTx + FU) was compared with DES alone or CTx + FU in 87 postmenopausal women with advanced breast cancer. Therapy was randomized according to the tumor estrogen-receptor (ER) status. In 30 patients with ER-rich tumors and 35 patients with ER-unknown tumors, combination therapy yielded a higher response rate than DES therapy (87% vs. 64% and 59% vs. 23%, respectively). The pooled data from these two groups of patients suggest that the improved response rate from DES + CTx + FU against DES becomes more apparent in patients with visceral involvement (89% vs. 47%) (P less than 0.025) and that patients treated initially with combination therapy (DES + CTx + FU) appeared to have a longer survival than those treated with sequential therapy (DES leads to CTx + FU) (P = 0.06). The survival data in 22 patients with receptor-poor tumors were significantly inferior to those with receptor-rich tumors (P = 0.001). The ER status and presence of visceral metastases are significant factors in the selection of treatment programs.