Cerebrospinal fluid (CSF) specimens from 22 allogeneic bone marrow transplant patients with central nervous system (CNS) symptoms (cases) and 107 patients who were immunocompromised but did not have CNS symptoms (controls) were assayed for human herpesvirus 6 (HHV-6) DNA. HHV-6 DNA was detected in CSF specimens from five (23%) of 22 cases and in CSF specimens from one (0.9%) of 107 controls (P < .001, Fisher's exact test). In addition, none of the five cases with HHV-6 DNA detected in CSF samples had any other identified cause of their CNS symptoms, and none of the other 11 cases with known causes for their CNS diseases had HHV-6 DNA detected in CSF samples (P = .03, Fisher's exact test). In three cases, HHV-6 variant B was identified, and the HHV-6 variant could not be defined in the other two cases. Prophylaxis with acyclovir did not prevent the occurrence of HHV-6-associated CNS disease after allogeneic bone marrow transplantation. Four cases' conditions were improved or they were cured after treatment with either ganciclovir or foscarnet, and one case died of CNS disease despite foscarnet treatment.