Abstract: After resolution of primary infection, human herpesvirus 6 (HHV-6) remains latent in the host and may reactivate during immunosuppression, inducing end-organ diseases. This case report describes a 56-year-old male with chronic myelomonocytic leukemia who received an allogeneic stem cell transplantation and developed chronic HHV-6 DNA in the serum. The patient was diagnosed with encephalitis. Although the patient stabilized on antiviral therapy, the viral load did not diminish. Semiquantitative polymerase chain reaction revealed that the stem cell donor cells contained germ line transmitted inherited HHV-6 (iHHV-6). Patients with iHHV-6 contain significant levels of HHV-6 DNA in the serum and cerebrospinal fluid regardless of health status due to normal cell lysis. Recently, with lymphocytes derived from iHHV-6 patients, the virus has been shown to reactivate and form new virus. Therefore, active HHV-6 infection in these cases is possible but impossible to determine from existing assays. Therefore, physicians must rely on clinical judgment to determine if the therapy would be beneficial. To complicate matters, some HHV-6 strains are resistant to foscarnet and ganciclovir. This report underscores the need for considering the diagnosis of iHHV-6 in patients harboring unusually high HHV-6 DNA levels and the need for better diagnostic tests to distinguish latent iHHV-6 from reactivated virus. The search for effective anti-HHV-6 drugs continues.