For patients with metastatic breast cancer (MBC) who undergo high-dose therapy with autologous peripheral blood progenitor cell (PBPC) transplantation, an important prerequisite is a mobilization regimen that efficiently mobilizes PBPCs while producing an effective anti-tumor effect. We prospectively evaluated ifosfamide-based chemotherapy for mobilization efficiency, toxicity and disease response in 37 patients. Patients received two cycles of the ifosfamide-based regimen; ifosfamide (5 g/m2 with conventional-dose cycle and 6 g/m2 with mobilization cycle) with either 50 mg/m2 doxorubicin (if limited prior anthracycline and/or progression more than 12 months after an anthracycline-based regimen) or 175 mg/m2 paclitaxel. For the mobilization cycle, all patients received additional G-CSF (10 μg/kg SC, daily) commencing 24 h after completion of chemotherapy. The target yield was >6 × 106 CD34+ cells/kg, sufficient to support the subsequent three cycles of high-dose therapy. The mobilization therapy was well tolerated and the peak days for peripheral blood (PB) CD34+ cells were days 10–13 with no significant differences in the PB CD34+ cells mobilization kinetics between the ifosfamide-doxorubicin vs ifosfamide-paclitaxel regimens. The median PBPC CD34+ cell content ranged from 2.9 to 4.0 × 106/kg per day during days 9–14. After a median of 3 (range 1–5) collection days, the median total CD34+ cell, CFU-GM and MNC for all 44 individual sets of collections was 9.2 × 106/kg (range 0.16–54.9), 37 × 104/kg (range 5.7–247) and 7.3 × 108/kg (range 2.1–26.1), respectively. The PBPC target yield was achieved in 35 of the 37 patients. The overall response rate for the 31 evaluable patients was 68% with 10% having progressive disease. Thirty-three patients have subsequently received high-dose therapy consisting of three planned cycles of high-dose ifosfamide, thiotepa and paclitaxel with each cycle supported with PBPCs. Rapid neutrophil and platelet recovery has been observed. Ifosfamide with G-CSF in combination with doxorubicin or paclitaxel achieves effective mobilization of PBPC and anti-tumor activity with minimal toxicity.