The anti-HBs response is bimodal with 4.2% of healthy persons producing no antibody and an additional 10% being hyporesponders. In the study of nonresponders, 2 extended haplotypes, [HLA-B8, SC01, DR3] and [HLA-B44, FC31, DR7], were found to be enriched in a pattern suggesting recessive inheritance. In the prospective immunization of homozygotes and heterozygotes for [HLA-B8, SC01, DR3], the homozygotes had less antibody than the heterozygotes. Family studies confirmed that the anti-HBs response was dominant and MHC linked, whereas nonresponse was recessive. In studies in vitro, it was shown that nonresponders failed to show lymphoproliferation in response to hepatitis B surface antigen (HBsAg) or an immunodominant nonapeptide. The lymphoproliferative response of responders to these stimuli was comparable and inhibited by anti-DR but not antibody to DQ or DP. The removal of CD8+ T cells did not produce lymphoproliferation to HBsAg in nonresponders. From mixtures of antigen-presenting cells and T cells from MHC-identical response discordant pairs, it was shown that the defect in the nonresponders was in their T cells and not their antigen-presenting cells, ruling out defective MHC binding or antigen processing as the basis of nonresponse.