BACKGROUND: The role of myeloablative chemotherapy in children with recurrent medulloblastoma and supratentorial primitive neuroectodermal tumors (MB/ST‐PNET) is controversial, in particular in patients who develop recurrent disease after craniospinal radiotherapy. METHODS: In this retrospective analysis, the authors investigated the outcome of children with recurrent MB/ST‐PNET who were referred for myeloablative chemotherapy and autologous hematopoietic progenitor cell rescue at Childrens Hospital Los Angeles. RESULTS: Thirty‐three children were referred for myeloablative chemotherapy: Fourteen of those children were never transplanted because of pre‐transplant adverse events, and 19, including 6 without and 13 with previous irradiation, underwent transplant. Conditioning regimens included a backbone of thiotepa, which was given either in a single cycle or in multiple sequential cycles. The 3‐year post‐transplant event‐free survival rate in unirradiated versus previously irradiated children was 83% ± 15% versus 20% ± 12%, respectively (P = .04). One child who had never been exposed to radiotherapy died of toxicity; the other children received post‐transplant radiotherapy and remained disease free. Nine previously irradiated children experienced 4 toxic deaths and 6 tumor recurrences (1 patient had both): An interval of <1 year between initial radiotherapy and myeloablative chemotherapy predicted a greater risk of toxic death (P = .02), whereas a history of meningeal metastases at diagnosis and a poor response to the initial rescue therapy predicted a greater risk of post‐transplant recurrence (P = .03 and P = .08, respectively). CONCLUSIONS: Myeloablative doses of thiotepa‐based chemotherapy and radiotherapy were able to cure most children who had radiotherapy‐naive, chemoresponsive recurrences. Children who developed recurrences after craniospinal radiotherapy had poorer outcomes; however, cure was possible in those who had good prognostic features at presentation, chemoresponsive recurrences, and a long interval between initial radiotherapy and myeloablative chemotherapy. Cancer 2009. © 2009 American Cancer Society.