The purpose of this study is to evaluate the efficacy of intermediate dose methotrexate (IDM), intrathecal (IT) methotrexate (Mtx), and citrovorum factor (CF) rescue in preventing central nervous system (CNS) involvement and improving the survival of children with non-Hodgkin's lymphoma (NHL). Sixty-four consecutive children were treated over a period of 5 years according to one of three regimens. Group I (19 patients) received induction and maintenance with Oncovin, Cytoxan and prednisone. One patient failed to go into remission, four relapsed locally, three had local and CNS relapse, six had solitary CNS relapse, two converted to leukemia and three patients are disease-free and off therapy 48, 64, and 76 months after diagnosis. Group II (seven patients) received, in addition to the above drugs, three doses of IT Mtx. One patient failed to go into remission, two had local relapse, one had local plus CNS relapse, one had CNS relapse only, one converted to leukemia and one patient is disease-free 56 months after diagnosis. Group III (38 patients) received an additional consolidation phase comprised of IDM with CF rescue plus three additional doses of IT Mtx. Three patients failed to go into remission, two converted to leukemia, three relapsed locally and the remaining 30 patients are disease-free, and off therapy 15 to 58 months (median 32 months) after diagnosis. We conclude that IDM with CF rescue plus IT Mtx is effective in preventing CNS involvement and improving disease-free survival in children with NHL.