The nucleotide sequence of a complete cDNA gene from a DP4-positive HLA-homozygous cell line, PGF, has been determined. This sequence is identical to the exon sequences in a genomic clone derived from another DP4-positive cell line, Priess. In contrast, our DP cDNA sequence shares only limited homology with partial cDNA sequences obtained from clones of three DP4-negative cell lines. On the basis of these results, we conclude that the phenotypic variation of DP alleles is directly attributable to the nucleotide sequence heterogeneity of DP-beta genes. That is, each phenotypic allelic form of DP antigen corresponds to a distinctly different DP-beta gene. Furthermore, this correspondence is found to be unaffected by the markers present at the DQ and DR loci, since the haplotypes of the PGF and Priess cell lines are, respectively, DR2,DQw1,DP4 and DR4,DQw3,DP4.