Five cases of fulminant hepatitis due to herpes simplex virus were identified among patients admitted to the Thomas E. Starzl Transplantation Institute between January 1991 and September 1994. The diagnosis was established in three of the five patients on the basis of transjugular liver biopsy specimen results. These three patients were treated with acyclovir; two survived and one required liver transplantation. Early histologic diagnosis, specific antiviral treatment, and liver transplantation in selected patients may improve the clinical outcome of this almost uniformly fatal disease.