A prospective randomized clinical trial was performed in 339 postmenopausal patients with advanced breast cancer. Two single modality treatment sequences, doxorubicin plus cyclophosphamide (AC) followed on failure by tamoxifen (TAM), and TAM followed by AC, were compared with combined modality chemo-endocrine therapy (TAM plus AC). The response rate to initial TAM (22.1%) was inferior to that for AC (45.1%), and for TAM plus AC (51.3%). However, patients randomized to the sequence TAM followed by AC showed a 42.5% overall tumor response to sequential protocol therapy, similar to the 46.9% for those randomized to AC followed by TAM. Furthermore, survival in all three arms was almost identical. Adverse prognostic factors for survival were liver metastases, short disease-free interval, poor performance status, and prior adjuvant chemotherapy. In no subgroup was significantly better survival associated with initial cytotoxic therapy. Endocrine therapy followed on failure by cytotoxics is appropriate for postmenopausal patients with advanced breast cancer.