A randomized clinical trial was performed to determine if combination therapy with doxorubicin, vincristine, and mitomycin C (DVM) was superior to doxorubicin alone in women with metastatic breast cancer for whom prior chemotherapy had failed. A total of 185 women were randomized to monthly courses of D (60 mg/m2, observation after 500 mg/m2); or D (50 mg/m2, maximum cumulative dose 500 mg/m2), V (1 mg/m2), and M (10 mg/m2, given every other cycle). Patients failing after D alone could receive V (1 mg weekly for 5 weeks, then 1.2 mg/m2 every 5 weeks) plus M (12 mg/m2 every 5 weeks). Objective responses were seen in 24 of 95 patients (25%) on D alone and 39 of 90 patients (43%) on DVM (two-sided p = 0.01). The time to disease progression distribution was significantly better for DVM (two-sided p = 0.02), but the magnitude of the advantage was small with the medians being 2.7 months for D and 4.2 months for DVM. There was no significant difference in survival between the two regimens. The degree of leukopenia was greater for DVM both in terms of median white blood cell nadir (1,300/microL versus 1,700/microL) and percentage of patients with a nadir less than 1,000/microL (33% versus 16%). A total of 45 patients received VM following D alone, and only seven (16%) achieved an objective response. We conclude that, despite a significantly higher response rate and longer time to progression, the degree of clinical benefit is not sufficient to recommend the combination of DVM over D alone as second-line therapy for women with metastatic breast cancer. The level of efficacy seen with VM as tertiary therapy is low and is of such a magnitude to suggest that V adds little but toxicity to M.