Cryptogenic chronic hepatitis (CCH) is diagnosed in patients with persistently elevated aminotransferase levels of unknown etiology. The workup of CCH patients must include a liver biopsy in order to exclude the largely unrecognized diagnosis of seronegative autoimmune hepatitis (SAIH). Patients with SAIH have demographic, biochemical, and histologic features of autoimmune hepatitis (AIH) and may be treated effectively with corticosteroids. Recognition and treatment of SAIH are necessary to prevent progression to end-stage liver disease. We performed a retrospective review of a database of 3507 patients seen at our institution over a 5-year period. Thirty patients with conventional AIH and an additional six patients with SAIH were identified. The two groups were similar with respect to mean age, gender, and baseline biochemistry. Of the 20 AIH patients who had pretreatment liver biopsies, 85% had moderate to severe interface hepatitis, compared to 83.3% of patients with SAIH. In the SAIH group, 83.3% had advanced fibrosis (stage 3 or 4), versus 40% in the conventional AIH group (P = 0.16). All patients were treated with corticosteroids followed by azathioprine. The mean time to remission (normal ALT) was similar in both groups, 2.6 vs. 2.7 months. Within 3 months, 88.9% of AIH patients and 66.7% of SAIH patients were in remission. We conclude that a trial of corticosteroids is a reasonable therapeutic measure in patients with chronic hepatitis that has features of AIH despite negative autoantibody markers. In most patients, clinical remission will be seen within 3 months, possibly avoiding progression to end-stage liver disease.