The effectiveness and superiority of sequential versus concurrent administration are unknown for regimens used in patients with operable, node-positive, early-stage breast cancer. There is evidence that the adjunctive use of ovarian ablation or suppression independent of chemotherapy may be associated with improved survival in premenopausal patients with hormone-receptor-positive breast cancer. The added benefit of ovarian suppression to chemotherapy outcomes in early-stage node-positive breast cancer is unclear. This randomized, multicenter, phase 3 trial compared the effect of sequential and concurrent regimens on overall survival and disease-free survival in patients with operable, node-positive, early-stage breast cancer. A total of 5351 patients were randomized to receive 1 of the following 3 regimens: (1) 4 cycles of doxorubicin plus cyclophosphamide followed by 4 cycles of docetaxel (the sequential-ACT regimen); (2) 4 cycles of doxorubicin plus docetaxel (the concurrent doxorubicin-docetaxel regimen); or (3) 4 cycles of doxorubicin plus cyclophosphamide plus docetaxel (the concurrent-ACT regimen). The primary aims of this trial were to determine whether the concurrent ACT regimen was more effective than the sequential ACT regimen and whether the doxorubicin-docetaxel regimen was as effective as the concurrent-ACT regimen. Secondary aims were to investigate the effect of amenorrhea on outcome end points of disease-free and overall survival. The patients were followed for up to 8 years. Treatment with sequential ACT was associated with a significant improvement in overall survival (8-year overall survival, 83%) compared with doxorubicin-docetaxel (overall survival, 79%); the hazard ratio (HR) was 0.83; P = 0.03. There was a nonsignificant improvement for concurrent ACT (overall survival, 79%; HR, 0.86; P = 0.09). With respect to disease-free survival, patients treated with sequential ACT (8-year disease-free survival, 74%) showed a significant reduction in the likelihood of disease recurrence, a second malignant condition, or death compared with either doxorubicin-docetaxel (disease-free survival, 69%; HR, 0.80; P = 0.001) or concurrent ACT (disease-free survival, 69%; HR, 0.83; P = 0.01). No difference was noted between the doxorubicin-docetaxel group and the concurrent-ACT group for either overall survival (HR, 0.96; P = 0.67) or disease-free survival (HR, 0.96; P = 0.58). There was improved overall and disease-free survival among women who had treatment-induced amenorrhea for 6 months or more, independent of the treatment and estrogen-receptor status. These findings show that the sequential administration of ACT is a superior treatment option for women with operable node-positive breast cancer to improve disease-free survival compared with doxorubicin-docetaxel or concurrent ACT, and to improve overall survival compared with doxorubicin-docetaxel. These data provide support for the added benefit of ovarian suppression induced by chemotherapy to improve survival, regardless of the regimen.