Introduction: Acute liver failure (ALF) is a life-threatening condition that remains challenging for physicians despite several advances in supportive care. Etiologies vary worldwide, with herpes simplex virus (HSV) hepatitis representing less than 1% of cases. Despite its low incidence, ALF is a lethal cause of acute necrotizing hepatitis and has a high mortality. Early antiviral treatment is beneficial for survival and decreased liver transplantation necessity. However, plasmapheresis, despite its theoretical potential benefit, is scarcely reported., Patient Concerns: A 25-year-old woman with no known disease presented with painful pharynx ulcers, increased transaminases and impaired liver function., Diagnosis: ALF due to a disseminated HSV-2 primary infection was diagnosed with a positive polymerase chain reaction for HSV-2 in the biopsied liver tissue and blood., Interventions: Empiric antiviral treatment was initiated. After clinical deterioration, plasmapheresis was also initiated., Outcomes: After 6 cycles of plasmapheresis and supportive care, the patient's condition improved without undergoing liver transplantation., Conclusions: ALF is a life-threatening condition, and HSV as an etiology must be suspected based on background, clinical manifestation, and laboratory information. The potential role of plasmapheresis in HSV hepatitis should be considered., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)