203 patients with inoperable non-small cell lung cancer (NSCLC) were randomized to receive ifosfamide (IFO) 2.5 g/m2 days 1-2 + epirubicin (EPI) 70 mg/m2 day 1 with cisplatin (DDP) 70 mg/m2 day 1 (arm IEP), or without cisplatin (arm IE). For uroprophylaxis, mesna i.v. 20% of IFO dose, hour 0 and 3, and oral, 40% of IFO dose, hour 6 and 9, days 1-2 was given. Cycles were repeated every 28 days. Four cycles were required for evaluation purposes. After completion of chemotherapy, external beam irradiation 40 Gy was given over 4 weeks for stage III B responders. Most of the patients with stable disease, partial response or complete response (CR) received 6 cycles. The median follow-up of the trial is 30 months. There were no differences in overall response rates: arm IEP: 52% (2% CR); arm IE: 51% (13.5% CR). Median time to progression was 6 months (arm IEP) and 4 months (arm IE) (p = 0.4844). Toxicity ranged from mild to moderate. Nephrotoxicity was not seen; only 6 patients had neurotoxic side effects of short duration. Median survival according to treatment was 12 months for IEP arm (12% at 2 years) and 10 months for IE arm (21% at 2 years). IFO/mesna+EPI or IFO/mesna, EPI plus DDP appeared to be an active and well tolerated combination for the treatment of NSCLC, with a good survival time.