Forty-six patients with chronic hepatitis delta virus infection were followed between 6 and 116 mo (mean = 32.8 mo; median = 24 mo). Nineteen patients (41%) demonstrated clinical courses with episodes of biochemical reactivation (ALT levels ≥ 10 times baseline values [group A]). Twenty-seven patients (59%) had stable clinical courses without biochemical reactivation (group B). Patients in group A were younger than those in group B (30.5 vs. 35.3 yr; p = 0.03), were less likely to be intravenous drug abusers (16% vs. 52%; p = 0.01) and were more likely to be homosexual (58% vs. 22%; p = 0.01). Serum hepatitis B virus DNA, hepatitis delta virus RNA, IgM antibody to HBc, HBeAg, antibody to HBe and IgG and IgM antibody to hepatitis delta virus were measured in all patients. In group A, these markers were studied before and during reactivation and during remission. In group B, these parameters were studied in a random fashion at 7- to 10-mo intervals. The presence of antibodies to human immunodeficiency virus and hepatitis C virus was assessed in all patients. A total of 38 biochemical reactivation episodes was noted among the 19 patients in group A. Eleven had sequential changes in hepatitis delta virus markers, suggesting that the exacerbations were due to hepatitis delta virus. In three, the sequential changes of viral markers were consistent with the exacerbations due to hepatitis B virus. In five other patients, no sequential changes in viral markers could be demonstrated to correlate with the biochemical exacerbations. Hepatitis C virus markers were found in 2 of the 19 patients; these two patients were in the group of 11 who had evidence of sequential changes of hepatitis delta virus markers with biochemical exacerbations. Of the patients in the control group (group B) who had stable biochemical courses, 10 had replication of hepatitis delta virus alone, four demonstrated replication of both hepatitis delta virus and hepatitis B virus and two demonstrated replication of hepatitis B virus alone. The viral markers did not reveal sequential or significant fluctuations in this group. In conclusion, the overall prevalence of biochemical reactivation episodes among our subjects with chronic hepatitis delta virus infection was 41%. In 58% of these patients, the episodes were related to hepatitis delta virus activity, whereas in 16% they were related to hepatitis B virus activity. Hepatitis C virus coinfection was rare in this study group. (HEPATOLOGY 1992;16:625–629.)