A prospective randomized trial was conducted comparing the clinical response of 60 patients with advanced breast cancer to a combination of adriamycin, cyclophosphamide, and oral ftorafur (ACF), or to a combination of ACF plus methotrexate (ACFM). The response rate was 12 of 28 (43%) in ACF and 18 of 30 (60%) in ACFM. Responses were seen more frequently in patients in whom fewer than two organs were involved, and responses at dominant metastatic sites were equal for the two arms. The response duration was 21+ (3.5–49.5+) months with ACF, as against 6.9 (1.9–30.8+) months with ACFM (P<0.05). the="" median="" survival="" time="" from="" start="" of="" therapy="" was="" 20.8+="" months="" for="" acf,="" while="" that="" for="" acfm="" was="" 13+="" months="" (statistically="" not="" significant).="" the="" major="" toxicities="" were="" hair="" loss,="" gi="" toxicity,="" and="" leukopenia.="" the="" response="" rate="" with="" acfm="" was="" higher="" than="" that="" with="" acf,="" but="" the="" addition="" of="" methotrexate="" to="" acf="" did="" not="" increase="" the="" complete="" response="" rate="" or="" prolong="" response="">