We conducted a phase II clinical trial using ifosfamide (IFX) as a single agent in cisplatin-refractory male germ cell tumor. Thirty patients with measurable disease were treated with IFX, 2 g/m2 intravenously (IV) for 5 consecutive days every 3 weeks. N-acetylcysteine, 2 g orally every 4 hours, was given as a uroprotective agent. All patients had previously been treated with cisplatin, vinblastine, and bleomycin, and all except two also had previously received etoposide. There were six partial responses (PR) and one complete response (CR) for an overall objective response rate of 23%. The median duration of response was 3.5 months (range, 2 to 5.5 months). The median survival time was 3.5 months (range, 2 to 14+ months). The toxicity of the regimen consisted of hematuria (65% of the patients), nausea and vomiting (43%), neutropenia (WBC less than 2,000; 52%), thrombocytopenia (platelet count less than 50,000; 20%), and nephrotoxicity (12%). Hematuria was dose related, occurring in 48% of courses using 2 g/m2/d v only 5% of courses at lower doses. Serious nephrotoxicity (creatinine level greater than 6.0 mg/mL) was observed in three patients with an elevated pretreatment serum creatinine level. In conclusion, IFX is an active agent in this heavily pretreated population with advanced refractory germ cell tumor.