Trimetrexate (TMTX), a lipophilic antifol, was evaluated in a Pediatric Oncology Group (POG) Phase I trial in children with refractory solid tumors. TMTX was administered intravenously daily x 5 every three weeks. Starting dose was 6.4 mg/m2/day. Dose was escalated by 20% until the maximal tolerated dose was reached. A total of 75 courses were administered to 26 children. The major toxicity was myelosuppression, of which neutropenia and thrombocytopenia were most prominent. Rash, mucositis, and transient liver enzyme elevations were infrequently seen. Responses were observed in children with brainstem glioma, neuroblastoma, and renal cell carcinoma. The recommended Phase II dose using this schedule is 9.2-11 mg/m2/day depending on how heavily the patient has been treated prior to initiating this therapy.