To determine the frequency and significance of alpha-fetoprotein elevation in severe hepatitis B surface antigen-negative chronic active hepatitis, 558 serum samples obtained from 83 patients were tested by an immunoenzymometric assay. All patients received corticosteroids and sampling occurred at 6-12-mo intervals during 96 +/- 6 mo of follow-up. Twenty-nine patients (35%) had an abnormal level. In 26 patients, the abnormality was at presentation. In 3 patients, the abnormality developed 11-127 mo later. Two of these patients had primary hepatocellular carcinoma. Serum aspartate aminotransferase levels were higher in patients with an alpha-fetoprotein elevation at presentation (p less than 0.02). After therapy, the alpha-fetoprotein level normalized and patients entering remission had lower levels than at entry (p less than 0.001). alpha-Fetoprotein levels, however, did not correlate closely with serum aspartate aminotransferase levels at entry nor did they distinguish patients with different patterns of histologic activity. Outcomes after therapy were similar in patients with and without alpha-fetoprotein elevation. Three patients (4%) developed primary hepatocellular carcinoma after 113 +/- 26 mo but only 2 had elevated alpha-fetoprotein levels. We conclude that elevation of the alpha-fetoprotein level occurs commonly at presentation. The abnormality frequently resolves after corticosteroid therapy and it does not have prognostic significance. An elevation that occurs after treatment suggests primary hepatocellular carcinoma.