From March, 1984, through June, 1987, 21 newly diagnosed children with high-risk medulloblastoma (Chang Stage T3 to T4) were treated on a 9-week postoperative, pre-irradiation chemotherapy regimen consisting of vincristine and cisplatin. The children over 2 years old then received radiation therapy. Six infants (aged 6 to 18 months) were maintained on chemotherapy consisting of MOP (nitrogen mustard, vincristine, and procarbazine) until the age of 2 years, at which time they were referred for irradiation. Of 13 children with measurable disease following surgery, five showed a definite response on computerized tomography scans to vincristine and cisplatin (one complete response and four partial responses) and five others showed clear marginal responses. Four of the six infants were disease-free at 19, 32, 35, and 57 months from diagnosis. One infant developed progressive disease at the completion of the vincristine and cisplatin course, and a second infant had progression during MOP administration. Three of the 21 children developed hearing loss within the speech frequencies during cisplatin treatments, but there were no other major toxicities. Fifteen children remained disease-free with a median follow-up period of 35 months (range 19 to 57 months). Chemotherapy given between surgery and radiotherapy may allow for the direct evaluation of a specific drug regimen and permit the postponement of radiation therapy in infants. Pre-irradiation vincristine and cisplatin was well tolerated and effective in shrinking the tumor in most children with medulloblastoma. Such chemotherapy regimens have the potential for extending long-term survival in high-risk children.