The major histocompatibility complex (HLA in humans) contains a relatively large set of gene loci in the HLA-D/DR region responsible for regulation of the immune response. The structural dissection of the protein products of these loci is a necessary accompaniment to understanding of this response. In this study, two subsets of HLA-DR-like molecules have been separated by using monoclonal antibodies, and their component alpha and beta chains have been subjected to amino acid terminal sequencing. The results from this sequencing experiment show three differences in the first 14 residues of the beta chains and no differences in the first 15 residues of the alpha chains. These data along with previous sequencing of the DC-1 antigen [Bono, M. R., & Strominger, J. L. (1982) Nature (London) 299, 836-838] demonstrate that three distinct subsets of HLA-DR-like antigens are expressed by a homozygous human lymphoblastoid cell line.