The complete coding sequences of cDNA clones encoding the DQw4 alpha and beta polypeptides have been determined from two individuals expressing the DRw18(3), DQw4 haplotype. Although the first domain nucleotide sequence of the DQ alpha cDNA is very similar to the DQw2 alpha sequence, the sequence of the membrane proximal region (encoding second domain, transmembrane, and cytoplasmic segments) is more similar to DQw3-like alpha-gene sequences. The nucleotide sequence of the membrane proximal region of the DQw4 beta gene is identical to the DQw8 sequence in contrast to the extensive differences in the region encoding the first domains of these polypeptides. These sequences have been used to determine the evolutionary relationships among DQ alpha and beta genes.