The response potential of inbred mouse strains against bovine type I procollagen and its separated structural domains, i.e., the globular procollagen peptide and the triple-helical collagen moiety, was compared by passive hemagglutination and radioimmune assays. Studies with congenic and recombinant lines and with backcross populations showed that the antibody response to procollagen peptide is under the control of a gene located in theIA, IB subregion of theH-2 complex. The strain distribution pattern of high response to the procollagen peptide is not identical to that of the high response to collagen. Both the procollagen peptide and procollagen are thymus-dependent antigens, since no response was observed in nude mice. Low response to procollagen peptide and/or collagen could be corrected in some, but not all mouse strains by using procollagen as immunogen. Strains which show low response against collagen but high response against procollagen were injected with collagen prior to a challenge with procollagen. This treatment reduced the antibody response to the procollagen peptide but not to collagen. Carrier and suppressor effects in the response to procollagen are apparently more complex than those observed in the response to synthetic peptides.