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To assess outcomes and define prognostic factors in patients with germ cell tumors who were treated with intensive post-remission high-dose chemotherapy (HDC) followed by hematopoietic stem cell transplantation (HSCT). Between 1985 and 2006, a total of 87 patients with germ cell tumors received second-line chemotherapy following a 6-month first-line HDC-containing regimen. Of these, 78 (90%) were evaluated for response and survival. End points were overall survival (OS), event-free survival (EFS), toxicity and factors predictive of response and survival. Median follow-up was 29.8 months (range, 0.4-188.1). Complete response (CR) was achieved in 21 patients (27%), 10 (17%) of whom later relapsed. Eleven patients relapsed (14%). Forty-one patients (53%) died, 15 (21%) within 12 months. After 1 year, OS and EFS were 81 and 64%, respectively. Univariate analysis identified only testicular primary tumor (p = 0.001), no viable tumor (p = 0.005) at second-line HDC and a nonfertilizing sperm dose of > 1 million (p = 0.05) to be significant factors predicting for poor outcome. The EFS of patients treated with melphalan only versus those treated with melphalan and cyclophosphamide was 20.9 and 56%, respectively (p = 0.01). Age and interval between the diagnosis of germ cell tumors and HDC were not prognostic factors. HDC-containing regimen followed by HSCT in germ cell tumors with relapsed or chemoresistant disease is feasible and seems to improve outcome after first-line HDC. Our analysis highlights the prognostic value of testicular primary tumor, demonstration of CR with second-line