We are determining the structure of the murine Ia alloantigens determined by the IA and IC subregions of the major histocompatibility complex (MHC) and comparing their structure to their human counterparts, i.e, DR antigens. Murine Ia and human DR antigens are isolated by indirect immunoprecipitation using highly specific allo and xenogeneic antisera, respectively. The molecular properties and N-terminal sequence of these cell surface proteins is determined using procedures that have previously provided detailed structural information for the K and D gene products of the MHC. Ia antigens determined by the IA and IC subregions each consist of two non-covalently associated molecules of 35,000–37,000 daltons and 28,000–29,000 daltons while the human DR alloantigens consist of two noncovalently associated molecules of 34,000 daltons and 29,000 daltons. Partial N-terminal sequence analysis indicates that while there is no apparent homology between the murine Ia alloantigens determined by the IA and IC subregions, the human DR alloantigen is structurally equivalent to the IC subregion alloantigen.