Four courses of ifosfamide with mesna given by intravenous infusions were combined with bolus doxorubicin in a phase II trial to treat patients with breast cancer. Ifosfamide can deplete intracellular glutathione levels and because doxorubicin resistance may be associated with elevated levels of intracellular glutathione these drugs were combined in an attempt to overcome clinical cytotoxic drug resistance. There were 31 women with poor prognosis advanced breast cancer in the study. Forty-five percent were younger than 40 years old, 68% had visceral dominant disease, 59% had more than two disease sites, and each of the five women tested had increased expression of primary tumor epidermal growth factor receptor. The objective response rate was 71% with manageable toxicity (95% confidence interval, 54% to 85%). The response rate in 22 patients not given prior chemotherapy was 72% and in 9 patients with cancers resistant to previous mitoxantrone monotherapy it was 67%. The high antitumor activity of this combination suggests further exploration of its use in breast cancer.