Abstract: Herpes simplex virus, an uncommon etiologic agent causing hepatitis, has been described in immunosuppressed, neonates, or pregnant patients as a fulminant disease with a relentless and fatal course in untreated individuals. Nonspecific signs and symptoms such as fever, anorexia, nausea, vomiting, abdominal pain, mucocutaneous lesions, elevations of aminotransferases, and leukopenia characterize herpetic hepatitis. We present a case of hepatic failure secondary to herpes simplex virus in a 35-year-old woman with human immunodeficiency virus infection in which definitive diagnosis was performed postmortem, with autopsy findings of massive hepatic necrosis with herpetic cytopathic effect and positive immunoperoxidase stains. Owing to its high mortality and available treatment, awareness and knowledge of this rare disease are critical for its early consideration in the differential diagnosis of any case of unexplained fulminant hepatitis. This will allow implementation of diagnostic tools, antiviral therapy, and referral for orthotopic liver transplantation, which proves lifesaving and positive impact prognosis.