Increased frequency of HLA-B8/DR3 has been reported in many organ-specific and systemic autoimmune diseases. Immune responsiveness in 11 normal subjects with and 22 without the B8/DR3 phenotype was studied. The IgA class immune response after immunization with the primary test immunogen alpha-Helix pomatia hemocyanin (HPH) was increased in B8/DR3-positive subjects compared to the non-B8/DR3 group. Also, IgG class antibody levels tended to be higher in the former group. The in vitro lymphocyte proliferative response to optimal concentrations of HPH did not differ between the groups nor did the response to allogeneic cells. Lymphocyte proliferation on stimulation with pokeweed mitogen and suboptimal concentration of phytohemagglutinin was increased in B8/DR3 individuals. It is concluded that the phenotype B8/DR3 is associated with a high humoral immune response.