To improve current adjuvant results in patients with resectable mammary carcinoma and more than three positive axillary lymph nodes.A prospective randomized study was carried out to compare the effectiveness of four courses of doxorubicin hydrochloride followed by eight courses of cyclophosphamide, methotrexate, and fluorouracil (CMF) (sequential regimen) vs two courses of CMF alternated with one course of doxorubicin for a total of 12 courses (alternating regimen). All drug courses were recycled every 3 weeks. The median duration of follow-up at the time of current analysis was 9 years.The study was conducted on patients operated on for primary unilateral breast cancer at the Istituto Nazionale Tumori of Milan, Italy. Adjuvant chemotherapy was delivered in the outpatient clinic of the Division of Medical Oncology.A total of 405 women were entered into the study, 403 of whom met the protocol criteria. Patient characteristics were fairly well balanced between the two treatment groups, with the exception of extent of nodal involvement: 38% with more than 10 positive nodes were randomized to the alternating regimen compared with 29% in the sequential regimen (P = .08).Relapse-free and total survival at 10 years after surgery estimated according to the Kaplan-Meier product limit method.Treatment outcome was significantly superior for patients who received the sequential regimen compared with those given the alternating chemotherapy. The relapse-free survival was 42% vs 28% (P = .002) and total survival was 58% vs 44% (P = .002), respectively. The benefit of the sequential regimen was evident in all patient subsets. Treatment was fairly well tolerated, but we documented four cases of congestive heart failure, which was fatal in two patients.Current findings indicate that in women with extensive nodal involvement, sequential chemotherapy with doxorubicin followed by CMF yields superior results compared with the alternating administration of the same regimens or with classical CMF.