It was previously demonstrated that the murine humoral immune responses to the common a and subtype-specific d determinants of HBsAg are H-2 restricted. The H-2q haplotype confers high responsiveness and the H-2s haplotype low responsiveness to nonresponsiveness to both determinants. We have now demonstrated that the H-2s haplotype also confers nonresponsiveness to the subtype-specific y determinant as well. Studies of H-2 congenic (nonresponder X responder)F1 and backcross mice indicated that responsiveness was inherited as a dominant trait, with no gene dosage effects observed. Qualitative characteristics of the humoral anti-a and anti-d responses were evaluated with respect to strain variation, kinetics, antigen specificity and antibody titer, affinity, and subclass distribution. Unique immune response patterns were observed for each H-2 haplotype studied. On the basis of these patterns, it was possible to construct a hierarchy of responsiveness to HBsAg of the ad subtype as follows: high responders, H-2q and H-2d; intermediate responders, H-2a greater than H-2b greater than H-2k; and nonresponders, H-2s.