High doses of combination alkylating agents have shown promise in the treatment of breast cancer but are complicated by significant toxicity. Busulfan and cyclophosphamide (BuCy) is a high-dose combination alkylating agent regimen that is well-tolerated when given for hematologic malignancy. We prospectively studied the effects of BuCy followed by autologous bone marrow transplant (ABMT) or peripheral blood progenitor cell (PBPC) rescue in 21 patients with metastatic breast cancer who had responded to either standard chemotherapy or radiotherapy. The mean patient age was 44 years. Nine patients were either estrogen- or progesterone-receptor positive, ten were negative, and two were unknown. Fourteen patients had local recurrence, ten had bone metastases, six had visceral disease, and two had a nonlocal soft tissue recurrence. Busulfan 16 mg/kg and cyclophosphamide 120 mg/kg (BuCy2) was given and followed by either ABMT, PBPC rescue, or both. Grade III to IV extramyeloid toxicity occurred in 6 (29%) patients. One patient died of hepatic venoocclusive disease but there was no other treatment-related mortality. Pulmonary infiltrates with hypoxia of uncertain origin developed in 2 patients after discharge. Of the 10 patients with measurable disease, 4 had complete responses, and 3 had partial responses to high-dose therapy for a total response rate of 70%. The estimated 2-year disease-free survival is 25% (95% CI = 6% to 44%). Our study found BuCy to be a well-tolerated preparative regimen for ABMT in the treatment of patients with metastatic breast cancer.