One-half of bone-marrow transplant (BMT) and stem-cell transplant recipients have reactivation of latent human herpesvirus (HHV)-6 2-4 weeks after transplant. Although the detection of viral DNA, RNA, and antigen in brain material confirmed active HHV-6 variant B infection, peak viral loads in cerebrospinal fluid (CSF) and serum occurred 2-4 weeks before death and decreased to low levels before or at autopsy. All autopsy samples consistently demonstrated HHV-6 active infection in the hippocampus. Astrocytic cells positive for viral antigen provided support for an HHV-6-specific tropism for hippocampal astrocytes. HHV-6 DNA in CSF and serum may not reflect the level of active viral infection in the brain after BMT.