The major histocompatibility complex (MHC) class II region is assumed to influence autoimmune diseases such as rheumatoid arthritis. In the mouse, the H‐2^q haplotype is associated with susceptibility to collagen‐induced arthritis, while the H‐2^p haplotype is not. The class II A molecules of these haplotypes differ by only four amino acids in the first domain of the β chain. To test if this difference accounts for the MHC influence on susceptibility to collagen‐induced arthritis, H‐2^p mice were made transgenic with an Ab^p gene altered to resemble the Ab^q gene. The transgenic A_β chain hybridized with the A_α^p chain and was shown to be physiologically expressed by testing antigen‐presentation capacity to A^q‐restricted T cell hybridomas and with FACS analyses. These transgenic mice developed an autoimmune response to type II collagen and also collagen‐induced arthritis. The data unequivocally suggest the Ab gene as a major genetic susceptibility locus for autoimmune collagen‐induced arthritis.