Human herpesvirus 6 (HHV-6) is a recently discovered virus the pathogenicity of which in solid organ transplant recipients has not been defined. We describe a unique febrile syndrome due to disseminated invasive variant B HHV-6 infection in a liver transplant recipient with evidence of direct tissue invasion by the virus. Acute febrile illness characterized by life-threatening thrombocytopenia, progressive encephalopathy and skin rash developed in association with invasive HHV-6 infection in a liver transplant recipient. HHV-6 was isolated from the patient's peripheral blood in cell culture; variant B HHV-6 DNA was detected in the patient's peripheral blood mononuclear cells (PBMC) at a concentration greater than 1000 virus genomes per 10(6) PBMC. A bone marrow biopsy was also positive for HHV-6, documenting direct tissue invasion. Intravenous ganciclovir for three weeks led to a prompt clinical response. Although larger studies are warranted, our case suggests that HHV-6 should be considered in the diagnostic evaluation of patients with fever, cytopenia, and encephalopathy, particularly since HHV-6 is susceptible to ganciclovir and foscarnet.