The genetic influences on the specific IgG antibody response to helical antigenic determinants of native soluble type III and V (AB2) human collagen have been studied in mice. H-2-linked Ir genes have been detected for each of these collagens, as have background effects. The alleles controlling high antibody responses can be distinguished from those previously described for bovine collagen type I and type I propeptide. Apparent two-gene complementation in the response to type V (AB2) may indicate that this antigen will be a useful probe in further studies of the complex nature of antigen presentation for T cell recognition. The present studies may facilitate the production of specific, high-affinity monoclonal antibodies for the human collagens which, in turn, will facilitate the study of connective tissue biology and pathology.