The therapeutic effectiveness of intermittent vs. continuous combination chemotherapy and of the substitution of adriamycin for methotrexate in a 5-drug regimen was evaluated in women with metastatic breast carcinoma. Patients were randomly allocated to receive continuous therapy with cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, prednisone ( CMFVP -C, 86 patients), intermittent CMFVP ( CMFVP -I, 109 patients), or intermittent CAFVP (107 patients). The CR + PR rate with CAFVP (71%) was superior to CMFVP -C (50%, p = 0.003) and to CMFVP -I (50%, p = 0.002). The remission duration with CAFVP (14 months, median) was superior to CMFVP -I (7 months) (p less than 0.01), and tended to be superior to CMFVP -C (9 months) (p = 0.07). There was a survival advantage of CAFVP (19 months, median) over CMFVP -I (13 months) (p = 0.01), but not over CMFVP -C (16 months) (p = 0.24). Among CR + PR patients, the survival with CAFVP (29 months, median) was superior (p = 0.02) to both CMFVP -I (18 months) and CMFVP -C (21 months). The CMFVP -C regimen was associated with the highest incidence of leukopenia and neurologic toxicity, but the lowest incidence of GI toxicity. The results indicate that the CAFVP regimen is well tolerated and is superior to the CMFVP regimens.