This study determined the maximum tolerated dose (MTD) of ifosfamide that could be given with high-dose cisplatin to non-small cell lung cancer (NSCLC) patients previously treated with non-platin-containing chemotherapy and to assess the efficacy of this combination. Twenty-three patients with inoperable NSCLC treated with one prior chemotherapy regimen received continuous infusion ifosfamide 1.2 g/m2 per day with MESNA for 5 days every 35 days and cisplatin 120 mg/m2. After one patient who received cisplatin as a single dose developed grade 4 nephrotoxicity and myelosuppression, cisplatin was given in four divided doses (30 mg/m2 per day) and the ifosfamide dose was lowered to 1.0 g/m2 per day, infused over 4 days. Dose-limiting grades 3 and 4 leukopenia was seen in 43%. A major objective response rate of 9% was observed. The 1-year survival was 30%, with a median survival of 6.4 months. The MTD of ifosfamide administered with cisplatin (30 mg/m2 per day for 4 consecutive days) to this population of patients is 1.0 g/m2 daily for 4 days. This combination produced limited anticancer activity and significant toxicity. Excessive toxicity was observed when cisplatin was given as a single dose with ifosfamide, and this schedule should not be used.