Our aim was to determine the efficacy of ifosfamide, mesna, and interferon alpha combination therapy in malignant mesothelioma (MM) patients. Fourty-two patients (39 evaluable) with histologically proven MM were enrolled into this study from January 1999 to October 2002. The drug schedule consisted of a combination of ifosfamide, 3000 mg/m(2) 1-3 d intravenous infusion (iv), the uroprotective agent mesna, 3000 mg/m(2) 1-3 d iv every 3 wk, and interferon alpha2a, 4.5 MU subcutaneously (sc) 3 d/wk for 6 mo as first-line chemotherapy. Overall, 140 cycles were administered to the 39 patients (median, 3.5 cycles; range, I to 6 cycles). Among the 39 patients, 8 partial remissions (PR) (21%) were observed. Thirteen patients (33%) had stable disease for at least 8 wk and 18 (46%) had progressive disease. Overall survival (OAS) and progression free survival (PFS) for all patients were 10.0 +/- 2.9 mo (95%CI 4.3-15.7) and 5.0 +/- 1.9 mo (95%CI 1.38-8.62), respectively. One and two year survival rates were calculated as 39% and 5%, respectively. All of the PR patients had the epithelial type of MM. Their survival time was 21.0 +/- 5.7 mo (95% CI 9.9-32.1) and significantly longer than that of nonresponders (p = 0.0061). The toxicity of the drug combination was mild and well tolerated. There were no treatment-related deaths. Grade 3-4 neutropenia and febrile neutropenia were seen in 10 patients (26%) and 3 patients (8%), respectively. Chemotherapy was stopped in three patients because of renal function deficiency. One of these patients-who had peritoneal MM-required hemodialysis. In conclusion, this combination therapy showed encouraging antitumor activity with modest toxicity.