Agents with broad cytotoxic activity, steep linear log dose-response relationships, relative non-cross-resistance, and nonoverlapping nonhematologic toxicities can be combined to create new high-dose combination regimens. We have previously reported phase I dose-escalation studies of ifosfamide, carboplatin, and the combination of the two. Etoposide has reported synergism with these alkylators and produces mucositis as its dose-limiting toxicity. The current study was designed to define the maximum tolerated doses of high-dose combination ifosfamide/carboplatin/etoposide (ICE), with stem cell support for amelioration of hematologic toxicity. Forty-eight adults with advanced malignancy received ICE chemotherapy by 96-hour continuous infusion. Initially, etoposide was added to fixed-dose ifosfamide and carboplatin, then the maximum tolerated dose of etoposide was fixed while doses of the alkylators were individually escalated. Autologous marrow, with or without peripheral blood progenitor cells, was reinfused 3 days after completing chemotherapy. The maximum tolerated doses of ifosfamide, carboplatin, and etoposide were identified as 16 g/m2, 1.8 g/m2, and 1.2 g/m2, respectively. Mortality was 4%. Patients who had prior cisplatin exposure were at increased risk for renal toxicity. If serum creatinine levels (monitored twice daily) rose sharply during chemotherapy, ifosfamide and carboplatin were immediately stopped. Severe multiorgan toxicity developed in the few patients who experienced early renal toxicity. Early stopping enhanced the safety of this regimen. Interpatient differences in chemotherapy drug metabolism or reduced renal clearance may predispose individuals to severe toxicity by increasing overall drug exposure. It was concluded that the ICE regimen is well tolerated and warrants further exploration as treatment of patients with small cell lung cancer, ovarian and germ cell carcinomas, and lymphomas in phase II trials.