A prospective randomized study was conducted in women with suboptimal (greater than or equal to 3 cm residual) Stage III, Stage IV, and recurrent ovarian adenocarcinoma to determine if combination chemotherapy is more effective than melphalan alone in achieving remission and improving survival. Of 233 evaluable patients with measurable disease, there were 64 treated with melphalan alone, of whom 20% achieved a clinical complete response and 17%, a partial response. Of the 97 patients receiving melphalan plus hexamethylmelamine, 28% achieved complete response compared with 32% of 72 patients given Adriamycin plus cyclophosphamide. The partial response rates for the combinations were 24% and 17%, respectively. The effect of these treatments was assessed in an additional 136 evaluable patients without measurable disease by progression-free interval and duration of survival. After statistically adjusting for distribution of cell type and grade, the clinical complete response rate for Adriamycin and cyclophosphamide (32%) in measurable cases was significantly higher (P = 0.04) than for melphalan alone. However, this combination did not improve median survival (12.3, 13.5, and 14.2 months, respectively, for M, M + H, and A + C). None of the other parameters showed a statistically significant advantage for combination chemotherapy, but the combinations caused more hematologic and gastrointestinal toxicity.