Herpes simplex hepatitis is a rare disease in adults and with high mortality (81%). Most cases are seen in immunocompromised hosts or in the third trimester of pregnancy. A 43-year-old woman with psoriatic arthritis, treated with prednisone and methotrexate (MTX), presented with an acute abdomen and elevated liver enzymes. The diagnosis was made by liver biopsy. MTX was stopped and acyclovir was started. The patient survived. The diagnosis of Herpes simplex should be suspected in immunocompromised hosts and established by liver biopsy and viral cultures. Treatment includes parenteral acyclovir and discontinuation or reduction of immunosuppressive therapy.