Ninety-six patients with metastatic breast cancer were entered in a prospectively randomized trial comparing a five-drug doxorubicin (Adriamycin)-containing regimen given in two different schedules. Both regimens included cyclophosphamide, methotrexate, 5-FU, prednisone, and doxorubicin. On one schedule, referred to as "combination" treatment, doxorubicin was given every 21 days and cyclophosphamide was given daily. On the less intensive "fixed-rotation" schedule, doxorubicin was given on alternative cycles every 42 days and cyclophosphamide was given for 21 days of the 42-day cycle. Response frequency and survival were comparable among patients receiving either regimen. Significantly less (P < 0.05) nausea and leukopenia occurred on the fixed-rotation schedule. Therefore, similar therapeutic benefit along with decreased toxicity was obtained by use of combination chemotherapy involving doxorubicin and cyclophosphamide given in the less intensive schedule.