A phase II clinical trial was designed to apply the treatment strategy of alternating non-cross-resistant chemotherapy regimens to patients with metastatic estrogen-receptor negative or hormone-refractory breast cancer. Twenty-six patients received Adriamycin and cyclophosphamide alternating at 3-week intervals with the combination of vinblastine, mitomycin-C, and 5-fluorouracil (5-FU). Toxicity was moderately severe. Two patients developed grade 2 and three developed grade 1 stomatitis. A single patient developed a WBC count of less than 1000/mm3, whereas five had a lowest recorded WBC count of 1,000-1,999/mm3. Two patients displayed thrombocytopenia of less than 50,000/mm3, one in conjunction with a fatal hemolytic-uremic syndrome. There were six complete and eight partial responses (PRs) for an objective response rate of 54% (64% of fully evaluable patients). The median survival after onset of protocol therapy was 13.3 months. These results are no better than those reported for other Adriamycin-containing regimens.