We provide evidence for an interaction between mouse class I major histocompatibility complex antigens and insulin receptors. Antibodies against class I but not class II major histocompatibility complex antigens immunoprecipitate photoaffinity-labeled hepatic insulin receptors. Haplotype specificity is demonstrated by reciprocal precipitation using anti-class I antibodies and three strains of mice. Antibodies against the 45-kDa products of either the H-2K or H-2D locus and rabbit anti-mouse beta 2-microglobulin antibodies were shown to precipitate insulin receptors. We also demonstrate the specific binding of 125I-labeled insulin and 125I-labeled epidermal growth factor, but not 125I-labeled glucagon or 125I-labeled atrial natriuretic factor, to solubilized plasma membranes immunoprecipitated with anti-H-2K antibody. These observations suggest a specific interaction between class I major histocompatibility complex antigens and certain hormone receptors.