Ex vivo experiments with vital brain tumor samples show that hyaluronidase enhances the permeation of carboplatin into tumor tissue with a matrix rich in hyaluronic acid. We achieved long-lasting second remissions for children with relapsed malignant brain tumors treated with carboplatin, etoposide and this enzyme. Thereafter, we initiated a pilot study where we added hyaluronidase to the first line standard therapy to prevent the deadly relapses right from the beginning. All 19 patients with malignant brain tumors admitted to our pediatric neurooncological center from 1992 to 1994 were included in the study. Kaplan-Meier estimation of event-free survival and overall survival after 3 years follow-up indicates a significantly better outcome for the hyaluronidase-treated group. The children receiving supportive hyaluronidase suffered significantly less relapses (P = 0.034) and had a significantly better chance for survival (P = 0.045) compared to the historical control of 21 children treated with the same standard regimen but without supportive hyaluronidase (product limit analysis and the log-rank test, P < 0.05). Children aged >3 years receiving hyaluronidase together with primary treatment seemed to gain the most benefit.