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In patients with acute liver failure (ALF) of unknown cause, viral infections are believed to be involved. This study investigates the involvement of human herpesvirus-6 (HHV-6).Thirty-two patients with ALF who underwent transplantations during a 6-year period were studied for viruses in biopsies from their explanted livers. Non-A to non-E hepatitis (unknown) ALF was the reason for transplantation in 15 patients, and another 17 patients with a known disease from the same time period served as controls. The explanted livers were examined for hepatitis viruses and other possible viral agents. HHV-6 antigens were demonstrated in the livers and blood mononuclear cells by immunoperoxidase staining.Of the 15 patients with ALF of unknown cause, 12 (80%) demonstrated HHV-6 antigens in the liver. Most of these patients (10/12) also demonstrated HHV-6 antigenemia. The predominant histologic finding of HHV-6 infection was moderate to severe portal lymphocytic infiltration. HHV-6 was found in 4 of 17 control patients, and cytomegalovirus was found in 2 of 17 control patients (in the blood and explanted liver). No other viruses were found in the livers of the patients with ALF.HHV-6 was found in most explanted livers of patients with ALF of unknown cause. HHV-6 antigenemia was associated with HHV-6 antigens in the liver. Only a few control patients displayed HHV-6 in the liver. These observations indicate that HHV-6 may be one of the causes of ALF.