OBJECTIVES: To determine the outcome of an expanded cohort of patients with relapsed germ cell tumors (GCT) treated with a salvage chemotherapy regimen consisting of irinotecan, paclitaxel and oxaliplatin (IPO) and assess the role of IPO as an alternative to standard cisplatin-based chemotherapy regimens in this setting. PATIENTS AND METHODS: The results of 72 consecutive patients were reviewed retrospectively. IPO was used either as a second-line treatment (n=29), of which 20 patients subsequently received high-dose chemotherapy (HDCT), or third-line (n=43), of which 32 patients proceeded to HDCT. RESULTS: The 2-year PFS and 3-year OS rates for the whole cohort were 30.2% (95%CI 17.3-40.5%) and 33.4% (95%CI: 20.1-43.8 %) respectively. CR was achieved in 3%, m-ve PR in 41%, m+ve PR in 18%, SD in 17% and PD in 20%. In the second-line setting, the 2-year PFS rate was 43.5% (95%CI: 21.7-60.8%) and 3-year OS 49.1% (95%CI: 24.2-65.1%). In the third-line setting, the 2-year PFS rate was 21.0% (95%CI 9.5-35.4%) and the 3-year OS rate was 23.9% (95%CI 11.7-38.2).According to the current international prognostic factor study group criteria for first relapse for the high and very high risk group the 2 year PFS rates were 50% and 30% respectively. There were 2 treatment related deaths from IPO, and 4 from HDCT. Grade 3 or 4 toxicities included neutropenia (35%), thrombocytopenia (18%), infection (15%), diarrhea (11%) and lethargy (8%).  CONCLUSIONS: IPO offers an effective, well-tolerated, non-nephrotoxic alternative to cisplatin-based salvage regimens for patients with relapsed GCT. It appears particularly useful in high risk patients and for those in whom cisplatin is ineffective or contra-indicated.