Interferon-beta (IFNβ) and natalizumab are commonly employed therapies for multiple sclerosis. IFNβ has been associated with rare hepatotoxicity, including autoimmune hepatitis in several patients. To date, serious hepatotoxicity has not been reported with natalizumab use. Here, we describe two patients with MS who developed autoimmune hepatitis shortly after being initiated on natalizumab. Case #1: A 26 y/o woman was admitted due to new onset of jaundice and fatigue. Her MS had been treated with interferon-beta-1a. This was discontinued two weeks prior to her presentation because of the development of a rash. One week prior to her presentation natalizumab was given for her MS. Initial laboratory data included an INR of 2, total bilirubin of 4.6 mg/dL, AST of 1863 U/L, ALT of 2212 U/L, and alkaline phosphatase of 74 U/L. Liver biopsy revealed centrilobular necrosis, lobular disarray with ballooning degeneration, mild canalicular cholestasis, and minimal microsteatosis (see image 1) thought consistent with AIH. Case #2: A 52 year-old woman with MS presented to the hospital with jaundice and abdominal pain. The patient's MS had been treated for several years with interferon-beta-1a and methotrexate. Three months prior to admission, natalizumab 400 mg was initiated intravenously on a monthly basis for worsening symptoms. After the second dose of natalizumab, the patient was noted to have an asymptomatic elevation in her liver function tests and methotrexate was discontinued. Shortly after the third dose of natalizumab, she devloped jaundice and worsening right upper quadrant abdominal pain. Laboratory data was significant for a total bilirubin of 6.6 mg/dL, AST 1984 U/L, ALT 1548 U/L, alkaline phosphatase 256 U/L, IgG 1860 mg/dL, anti-nuclear antibody 1:640 titer, and INR of 1.3. Liver biopsy revealed chronic hepatitis with marked portal inflammation with prominent plasmacytic infiltrate consistent with autoimmune hepatitis (see image 2). Discussion: In this report, we describe two cases of autoimmune hepatitis following the administration of natalizumab for treatment of MS. Based on these reports, we would strongly suggest that liver function testing be closely monitored in all patients for evidence of acute hepatitis and liver dysfunction during treatment with natalizumab.