Purpose: To determine the relative efficacy of a cyclophosphamide epirubicin and fluorouracil (CEF) regimen compared with an intravenous (IV) cyclophosphamide, methotrexate, and fluorouracil (CMF) combination in metastatic breast cancer. Patients and Methods: Patients were randomized to receive either CEF (cyclophosphamide 400 mg/m2 IV, epirubicin 50 mg/m2 IV, and fluorouracil 500 mg/m2 IV an days 1 and 8), or CMF (cyclophosphamide 500 mg/m2 IV, methotrexate 40 mg/m2 IV, and fluorouracil 600 mg/m2 IV an days 1 and 8). Treatment was given in 3- to 4-week cycles for a total of six to nine cycles. Results: A total of 460 patients (223 CEF and 237 CMF) were randomized. Overall response rate was superior for CEF than CMF in all randomized patients (57% v 46%, respectively; P = .01) and in the assessable subset (66% v 52%, respectively; P = .005). With a median follow-up of more than 20 months, time to progression (TTP) was significantly longer with CEF than CMF (median 8.9 v 6.3 months, respectively; P = .0064), as was time to treatment failure (TTF) (median 6.2 v 5.0 months, respectiveiy; P = .01). Significant survival differences were not observed between CEF and CMF (median 20.1 v 18.2 months, respectively; P = .23). Granulocytopenia and infections were similar in both arms. Grade 3/4 nausea/vomiting and alopecia were more frequent with CEF, whereas diarrhea was more frequent with CMF. Cardiac toxicity, primarily asymptomatic, reguired withdrawal from study of 15 patients on CEF (7%) and one patient on CMF. Conclusion: This CEF regimen safely provides significantly better tumor control than CMF, manifest as a higher response rate, and longer TTP and TTF, but not survival, when used as first-line chemotherapy for metastatic breast cancer. © 2001 by American Society of Clinical Oncology.