Introduction: Development of systemic HSV infection, including hepatitis, is typically seen in immunocompromised patients (HIV, malignancy, immunosuppressive treatment, malnutrition, pregnancy, advanced age). HSV hepatitis is characteristically an anicteric hepatitis with markedly elevated aminotransferases (> 3000) and frequent systemic symptoms (fever). High index of clinical suspicion is very important, since HSV hepatitis can be associated with high mortality, and prompt treatment with Acyclovir can be life-saving. Recognizing HSV hepatitis is particularly important in patients without known risk factors for HSV dissemination. Diagnosing HSV hepatitis in such patients should prompt a search for the presence of an indolent immune compromise. Case: We present a case of a 55-year-old Caucasian male with no significant medical history who presented with eight days of fever, rigors, nausea, and vomiting. Physical exam: BP 97/61, HR 80, T 101.6, macular rash on the face and chest; otherwise unremarkable. He was started on broad spectrum antibiotics for presumed infection, but his fever continued. On hospital day two, he developed confusion and somnolence; ammonia was 37. Mental status improved with lactulose. The patient developed vesicular rash on the back during the hospital stay. Initial lab work-up revealed WBC 6, aminotransferases 700s, bilirubin 1.4, INR 1.1. Blood and urine cultures, hepatitis A/B/C serology, ANA, AMA, immunoglobulins, HIV, EBV, and CMV were all negative. Acute HSV serology, however, was positive, and HSV-1 DNA was positive as well. Aminotransferases continued to increase: by hospital day six, AST and ALT had risen to 3,800 and 1,700; INR to 1.5; bilirubin remained 1.4. Atypical lymphocytes and smudge cells were repeatedly noted on peripheral smear. Abdominal CT scan showed mild ascites and pancreatic, portal, and caval lymphadenopathy. Liver biopsy was performed, and revealed well-circumscribed foci of coagulative necrosis consistent with herpes viral injury; immunohistochemical stain was strongly positive for HSV within the necrotic areas. A swab from a vesicle on the back tested positive for HSV by direct flourescent antibody test. Therapy with IV Acyclovir was initiated, with rapid improvement in clinical status, aminotransferases, and coagulopathy. The persistent evidence of atypical lymphocytes and smudge cells in this patient with HSV hepatitis justified additional workup. The patient was found to have monoclonal gammopathy and chronic lymphocytic leukemia, for which he is currently being followed up by Hematology.