Studies were undertaken to determine whether anti-idiotypic antibody (anti-Id) against antibody to hepatitis B surface antigen (anti-HBs) could modulate in vitro anti-HBs production by human peripheral blood mononuclear cells stimulated with pokeweed mitogen. Peripheral blood mononuclear cells from patients positive for serum anti-HBs produced significantly increased amounts of anti-HBs by the addition of IgG fraction of anti-anti-HBs as well as purified HBsAg in a soluble form when compared to those in cultures with pokeweed mitogen alone. F(ab')2 but not Fc fragments of anti-anti-HBs significantly enhanced anti-HBs levels in cultures. Anti-anti-HBs or HBsAg alone, however, did not induce anti-HBs production. Anti-HBs production was not observed by the additions of these additives when peripheral blood mononuclear cells from chronic HBsAg carriers and control individuals were used. These findings indicate that anti-Id modulates the immune response to HBsAg.