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Post-transplant lymphoproliferative disorder (PTLD) is a malignancy that occurs in 2-20% of solid organ transplant recipients. Isolated, primary central nervous system (PCNS) PTLD is exceedingly rare, with existing data limited to case reports and case series. The diagnosis of PCNS PTLD is difficult to diagnose given 1) non-specific clinical presentation and 2) burden of immunosuppression broadens diagnostic possibilities, often requiring extensive testing to reach a definitive diagnosis. We present the first known case of isolated PCNS PTLD after liver transplantation safely treated with methotrexate. Our case highlights the complex diagnostic and treatment considerations in the setting of immunosuppression and maintenance of adequate graft function. [ABSTRACT FROM AUTHOR]