High-dose chemotherapy and autologous hemopoietic stem cell transplantation (HSCT) may provide durable progression-free survival in some patients with stage IV breast cancer (S4Brca). We have studied a new four-drug intensive preparative regimen with HSCT in a group of 158 women with S4Brca to define the risk and potential benefit of this regimen in this patient population. From May 1988 through May 1997, 158 women with S4Brca at a single center were treated with cisplatin, etoposide, thiotepa, and cyclophosphamide (PETCy) plus autologous HSCT Eligible patients were also treated with posttransplant involved-field radiation therapy. Patients with estrogen-receptor positive tumors not previously treated with tamoxifen also received this therapy for 5 years following transplantation. All patients experienced significant toxicity requiring blood-product support and parenteral nutrition. Eighteen patients (11%) died of regimen-related toxic events. With a median follow-up of 540 days for surviving patients, a retrospective Kaplan-Meier analysis projects an overall survival of 38+/-8.5% (95% CI) at 890 days with a maximum follow-up of 8.8 years. For 52 patients in sensitive relapse, the median event-free survival time is 767 days, with 46.2+/-15.3% (95% CI) predicted to be alive at 884 days with a maximal follow-up of almost 9 years. Nearly one-half of patients in this study with S4Brca in sensitive relapse have experienced durable remissions following PETCy ablation and HSCT. Although toxicity is significant, the PETCy regimen produces a favorable balance between efficacy (event-free survival) and treatment failure (relapse + regimen-related toxic death) compared with published results. These data suggest that within the high-dose range for preparative therapy, a steep dose-response may exist for breast cancer. Trials comparing the dose intensity of preparative regimens are warranted.