Ifosfamide has shown promising single-agent activity in non-small cell lung cancer. We combined ifosfamide (1,800 mg/m2, plus 1,100 mg/m2 of mesna by intravenous continuous infusion daily for 3 days) with cisplatin (20 mg/m2 intravenously for 3 days) and etoposide (80 mg/m2 intravenously for 3 days) and treated 41 patients with recurrent or metastatic non-small cell lung cancer who had received no prior systemic chemotherapy. Fifteen (40.5%) of the 37 evaluable patients had objective responses (one complete and 14 partial). Patients with a good Zubrod performance status (ie, 0 or 1) had a higher response rate than those with poor performance status (ie, 2) (11 of 21 [52.4%] v 4 of 16 [25.0%]), but the difference was not statistically significant (P = .09). Median survival was 28 weeks for all patients and 59+ weeks for responders, with 11 patients still alive after a median follow-up of 59 weeks (range, 51 to 77 weeks). Overall, treatment was well tolerated, with granulocytopenia being the most frequent toxicity. Considering the pooled response rate of 32% with a cisplatin/etoposide regimen and the previous experience from our institution, the results with this three-drug regimen are encouraging, and its further investigation is warranted, particularly for patients who have good performance status and in a neoadjuvant setting.