The purpose of the study was to establish the maximum tolerated dose of ifosfamide, administered over 72 hr, in metastatic breast cancer patients, pretreated with chemotherapy. Ifosfamide and mesna were given at the same dose, in the same solution, using a portable Pharmacia CADD-1 pump connected to a central venous access, at three dose levels: 7.5 g/m2 (6 patients), 9 g/m2 (8 patients), 10.5 g/m2 (3 patients); the courses were repeated every 3 weeks. Seventeen patients with a median age of 55 years (range, 34-68) and median performance status of 0 (range, 0-2) were treated. The patients were pretreated with a median of 2 (range, 1-3) prior regimens including anthracyclines in 14 patients and paclitaxel in 9. Dose-limiting toxicity was defined as the occurrence of any of the following events in > or = 2/6 patients: absolute neutrophil count < 500/ml for > 7 days or < 100/ml for > 3 days; febrile neutropenia; grade 4 thrombocytopenia; any grade > or = 3 nonhematologic toxicity. The dose-limiting toxicities were febrile neutropenia and grade 4 thrombocytopenia in 2/3 patients treated at 10.5 g/m2. Seven patients achieved an objective response (response rate 41%; 95% CI, 18% to 67%). We conclude that 72-hr infusion of ifosfamide is feasible in ambulatory patients. The recommended dose for phase II studies is 9 g/m2, with courses repeated every 21 days.