Cell-mediated and humoral immune responses to heterologous insulins in mice are controlled by H-2-linked, dominant, immune response (Ir) genes. For example, mice bearing the H-2(d) haplotype develop T cell proliferative responses and produce antibody after injection with porcine insulin, whereas mice bearing other H-2 haplotypes do not. Data presented in this communication demonstrate that homozygous and heterozygous H-2(d) mice produce insulin-binding antibodies when immunized with porcine insulin or proinsulin. Some (H-2(b,k,s)) insulin-nonresponder mice produce insulin-binding antibodies after injection of proinsulin, whereas other insulin-nonresponder strains (H-2(q)) do not. All strains, except homozygous H-2(q) mice, produce antibodies specific for proinsulin, suggesting that the response to porcine proinsulin is also controlled by H-2-linked Ir genes. More importantly, F1 hybrids between insulin-nonresponder C57BL/10 (H-2(b)) and DBA/1 (H-2(q)) produce no insulin-binding antibodies when injected with proinsulin, despite the fact that proinsulin-binding antibodies are produced by these mice.