Background: This randomized, multicenter, phase III trial compared doxorubicin plus cyclophosphamide (AC), single-agent docetaxel (D), and an alternating regimen of AC and docetaxel (AC–D) as first-line chemotherapy in metastatic breast cancer (MBC). Patients and methods: Patients with MBC resistant to endocrine therapy were entered in a randomized study to receive either six cycles of AC (doxorubicin 40mg/m2 plus cyclophosphamide 500mg/m2), D (60mg/m2), or alternating treatment with AC–D (i.e. three cycles of AC and three cycles of D). Treatment was administered every 3 weeks. Results: A total of 441 patients were entered in a randomized study. Response rates were 30% for AC, 41% for D, and 35% for AC–D. The median times to treatment failure (TTFs) were 6.4, 6.4, and 6.7 months (one-sided log-rank test, P=0.13 for AC versus D, P=0.14 for AC versus AC–D) and median overall survival (OS) was 22.6, 25.7, and 25.0 months (P=0.09 for AC versus D, P=0.13 for AC versus AC–D) in the AC, D, and AC–D, respectively. Conclusion: There was no difference in the TTF among the three arms. However, there was a trend toward a better response and better OS in the D than in the AC.