Two patients with a plausible diagnosis of central nervous system graft-versus-host disease (CNS-GVHD) are described. Both presented with neurological manifestations 6 and 18 months following allogeneic transplant with hemiparesis, seizure, encephalopathy and magnetic resonance findings of hyperintense white matter lesions on T-2 weighed images. Brain biopsy in one and autopsy in the other revealed profound perivascular lymphocytic infiltrates composed predominantly of T-lymphocytes that were of donor origin. Although an unequivocal diagnosis of CNS-GVHD is difficult to establish, the transplantation community should be aware of this controversial entity.