In hepatitis B virus (HBV) infection correlation of disease activity with major histocompatibility complex (MHC) antigens has been suggested. However, no data are available regarding the nature and regulation of the immune response to the surface viral protein (HBsAg). This consideration and the current emphasis on production of an HBV vaccine led us to investigate the humoral immune response to HBsAg in inbred strains of mice to assess genetic factors that may regulate the humoral anti-HBs response. Studies with H-2 congenic and noncongenic inbred strains revealed the T-dependent humoral immune responses to the group-specific a and subtype-specific d determinants of HBsAg are regulated by gene(s) mapping to the murine MHC. The H-2q haplotype conferred high responsiveness, the H-2s,f haplotypes conferred low to nonresponsiveness, and the H-2a,b,d,k haplotypes were intermediate. Studies of H-2 recombinant strains allowed tentative mapping of regulation of the anti-a response and possibly the anti-d response to the K/I-A, I-B region of the MHC. The H-2-restricted regulation of the humoral immune response to HBsAg was circumvented by immunization with 10-fold higher HBsAg doses. These findings demonstrate a clear linkage between the murine MHC and the regulation of the immune response to specific determinants on HBsAg.