To determine the possible changes in the presence and level of anti-idiotype (anti-Id) antibodies against anti-HBs induced by recombinant interferon (rIFN) therapy in chronic hepatitis B virus (HBV) infection, a study of patients under rIFN treatment has been carried out. A total of 62 (38 treated and 24 controls), HBeAg and HBV-DNA positive HBsAg carriers were tested serially for the presence of IgG and IgM anti-Id antibodies. According to serological evolution, treated patients were divided in responders (HBeAg and HBV-DNA became negative) (n = 18) and nonresponders (n = 20). Control patients were also classified as having spontaneous seroconversion (n = 11) and without changes (n = 13). Basally all patients had IgG and IgM anti-Id. At the end of the follow-up period (15th month), a significant decrease was observed in the percentage of cases positive to anti-Id among rIFN-responders (IgG, 67%, p less than 0.01; IgM, 44%, p less than 0.001). In contrast, only one nonresponder lost IgM anti-Id during the study. Among controls, only one with spontaneous loss of HBV-DNA and HBeAg clearance became negative to both IgG and IgM anti-Id. In addition, in the basal sample, the rIFN-responders had significantly lower anti-Id levels than the nonresponders (p less than 0.05). Similar results were obtained when comparing the controls with or without spontaneous response (p less than 0.05). Furthermore, a significant decrease in the anti-Id levels among the rIFN responders at the 9th month was detected (p less than 0.01). In summary, the anti-Id antibodies decreased significantly in patients who became HBV-DNA negative following rIFN administration. This result confirms the close relationship between HBV replication and the anti-idiotype against anti-HBs.