Patients with advanced breast cancer who had not previously received chemotherapy were treated on a three-arm prospective study: adriamycin day 1 plus 5-FU on day 1 and 8 (AF), adriamycin day 1, plus 5-FU day 1 and 8, and cyclophosphamide day 1 (AFC), and adriamycin day 1 plus 5-FU day 1 and 8, cyclophosphamide day 1 and methotrexate day 1 (AFCM). These courses were repeated every 21 days. The response rate was 44/105 (42%) AF, 44/103 (43%) AFC and 52/105 (49%) AFCM. The length of response was 22, 33 and 35 weeks, respectively, for AF, AFC and AFCM (P = 0.21). The median survival, 64 weeks, was equal in all three limbs. The major toxicity was leukopenia. Twenty-eight percent developed a WBC of less than 2,000/microliter, which resulted in seven deaths (2.2%).