Posttransplant lymphoproliferative disorder (PTLD) is an uncommon neoplastic complication of kidney transplantation, affecting about 1% of recipients. It is generally associated with Epstein-Barr virus (EBV) infection of B-lineage lymphocytes. Central nervous system (CNS) involvement is rare. There is little clinical experience with treatment of CNS PTLD due to the relative rarity of the disease other than reduction or withdrawal of immunosuppression, but it is usually fatal. We describe six patients with renal allografts and histologically proven isolated CNS PTLD. Tissue analysis from the biopsy specimens was positive for EBV material in five of the six patients. All six patients were treated with high-dose intravenous methotrexate (HD IV MTX). Methotrexate was initiated at 8 g/m 2, with later adjustments for creatinine clearance. With MTX therapy, four patients have had a sustained complete response, and two had progressive disease and were referred for radiation therapy. This finding suggests a subgroup of patients may benefit from MTX but our case series is inadequate to describe overall efficacy. No unexpected toxicities were encountered in 37 courses of treatment. HD IV MTX chemotherapy should be considered as an alternative for treatment of CNS PTLD. © 2009 The American Society of Transplantation and the American Society of Transplant Surgeons.