Despite extensive analysis of the incidence of HLA-DR and HLA-DQ allele frequencies in defined autoimmune disease groups, there is very little information available on HLA-DP allele frequencies. This is largely because HLA-DP typing has until recently been restricted to primed lymphocyte typing (PLT). However, allelic polymorphism of the HLA-DP subregion can now be studied by Southern blot analysis or genotyping with DPA1 and DPB1 probes. By direct counting of allele-specific DNA fragments, we have analyzed the frequencies of five major DP genotypes (DPw1, DPw2, DPw3/6, DPw4, and DPw5), in a large number of Caucasoid rheumatoid arthritis (RA) patients (n = 74), and controls (n = 91). The predicted frequency of DP alleles in both patient and control groups was comparable to PLT-determined DP allele frequencies in normal Caucasoids. However, the gene frequency of DPw4 was increased in the RA patients, with 51% of the patients studied scoring as DPw4, 4 homozygotes. With the exception of one possible combination (DPw5 and DRw6) in the controls, no significant linkage disequilibrium was detected between DP and DR alleles in either patient or control groups. Thus the prevalence of DPw4 in the RA patients is independent of any disease association with the DR loci, and may represent a new class II association with RA.