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BACKGROUND: Herpes simplex virus (HSV) infections are frequent. However, HSV hepatitis is rare and may lead to a life-threatening condition. CASE REPORT: A 68-year-old patient with a locally advanced and inoperable esophageal carcinoma was treated with induction chemotherapy and combined chemoradiation. After a total of 9 weeks of treatment, he developed fulminant liver failure of unknown origin and died a few days later. Surprisingly, the post mortem examination revealed an HSV infection of the esophagus and an HSV-associated necrotisizing hepatitis. CONCLUSION: In this immunocompromised patient, we postulate an HSV-associated esophagitis that led to viremia and fulminant hepatitis. Especially in immunocompromised hosts, HSV hepatitis should be considered in the differential diagnosis in patients with anicteric hepatitis and marked elevation of transaminases. A liver biopsy is the quickest and most definitive diagnostic tool to diagnose HSV hepatitis. If this is not possible because of severe coagulopathy, polymerase chain reaction for HSV DNA should be performed. Awaiting diagnosis, a prompt empirical treatment with acyclovir has to be discussed in case of a characteristic biochemical profile.