We undertook a phase I-II trail of loco-regional mitoxantrone in 12 patients affected by malignant gliomas. Mitoxantrone was delivered at tumor recurrence by Ommaya reservoir, with 2 cycles and a 1 month interval between each cycle, in conjunction with systemic chemotherapy (8 pts) or not (4 pts). Treatment tolerability was good, and 9 of the patients showed either response or stable disease at the end of the treatment schedule. Regardless of associated chemotherapy, time to further tumor progression was at 6 months. A combination of early systemic and loco-regional chemotherapy with surgery and radiotherapy seems worth while pursuing in the therapeutic approach to malignant gliomas.