The aim of this paper is to evaluate the activity of ifosfamide in previously treated patients with metastatic breast cancer. From June 1991 through November 1992, 29 patients with metastatic breast cancer were treated with single-agent ifosfamide, 2 g/m2 intravenously daily for 5 days, with mesna support. All patients had previously received chemotherapy; all but one had previously received cyclophosphamide. The ifosfamide-mesna regimen was the first-line metastatic regimen in 15 patients, the second-line metastatic regimen in 13 patients, and the third-line metastatic regimen in one patient. Two partial remissions (7%) were observed; both occurred in the first-line metastatic group. The partial remissions were noted in patients who had completed adjuvant cyclophosphamide therapy 60 and 91 months earlier. Both responses were seen in lung metastases. The response durations were 5 and 8 months on continued therapy. The main adverse effects were granulocytopenia, fatigue, nausea, vomiting, and stomatitis. At the dose used in this study, ifosfamide and mesna given without growth-factor support resulted in significant myelosuppression and produced only two partial remissions (7%) in 29 patients. Further study of ifosfamide as an isolated agent in previously treated patients is not warranted.