Human herpesvirus-6 (HHV-6), a beta herpesvirus closely related to cytomegalovirus (CMV), infects the majority of the population in childhood. Human herpesvirus-6 can be reactivated in the immunosuppressed patient. After bone marrow and orthotopic liver transplant, it has been linked to various clinical syndromes, including undifferentiated febrile illness, encephalitis, pneumonitis and bone marrow suppression. To date its infectious role after orthotopic heart transplant has not been well documented. We present the case of a 32-year-old cardiac transplant recipient who initially presented 8 weeks after his transplant with high fever and headache. He developed increasing confusion, pulmonary infiltrates and neutropenia. Cytomegalovirus viral loads were negative. Polymerase chain reaction (PCR) of blood and cerebrospinal fluid detected HHV-6 DNA, consistent with HHV-6-related encephalitis, pneumonitis and bone marrow suppression. He was treated with foscarnet with gradual improvement in clinical status. We review the literature on the significance of this virus post cardiac transplant.