The class II products of the major histocompatibility complex, also called Ia antigens, are composed of two polypeptide chains, the alpha and beta chains, both encoded within the major histocompatibility complex. In man, the class II antigens can be divided into three biochemically distinct groups called HLA-DR, HLA-DC, and HLA-SB. Our isolation of cDNA clones for the polymorphic beta chain of HLA-DR and HLA-DC has allowed us to study the organization of the class II genes. Here we identify the HLA-SB beta-chain gene in recombinant clones from a cosmid library generated from a consanguineous homozygous B-cell line. The SB beta-chain gene is linked to the SB alpha-chain gene and the two genes are in opposite orientation. A second SB beta-chain gene, corresponding to a new SB beta II locus, has also been identified and cloned. The SB beta-chain genes show much less allelic restriction site polymorphism than the genes for the beta chains of HLA-DR or HLA-DC.