PURPOSE: To compare two adjuvant combination chemotherapies, cyclophosphamide, methotrexate, and fluorouracil (CMF) and chlorambucil, methotrexate, and fluorouracil (LMF), for patients who had undergone potentially curative surgery for unilateral breast cancer, in terms of relapse, survival, and toxicity. PATIENTS AND METHODS: Selection criteria was as follows: stage pT1-3a, N+ or N-, M0, less than 72 years of age. Eligible patients were randomized to receive either CMF (cyclophosphamide 100 mg/m2 orally on days 1 to 14, methotrexate 40 mg/m2 intravenously (I.V.) on days 1 and 8, fluorouracil 600 mg/m2 I.V. on days 1 and 8) or LMF (Leukeran [Wellcome A.G., Bern, Switzerland] 5 mg/m2 orally on days 1 to 14 with the some I.V. cytostatic drugs). Follow-up examinations were performed every 3 months during the first 3 years after mastectomy, and every 6 months thereafter. RESULTS: A total of 246 patients were randomized, of whom 232 who were fully eligible and contribute to the analyses presented here. No statistically significant difference in favor of adjuvant CMF over LMF emerges after a median follow-up duration of 11.2 years, for either overall survival (P = .15) or disease-free survival (P = .14). A consistent trend suggestive of a possible relative benefit associated with CMF should be pointed out. However, CMF presents a significantly worse toxicity profile as concerns hematologic parameters as well as alopecia, nausea, and vomiting. CONCLUSION: This prospective trial has not identified a statistically significant difference in disease-free survival or overall survival between the two adjuvant regimens LMF and CMF. Although a trend in favor of CMF has been observed in premenopausal patients, this has to be weighted against its definitely more pronounced toxicity profile.