The association of HLA-DR4 with rheumatoid arthritis strongly implicates genes of the major histocompatibility complex (MHC) as contributing to disease susceptibility. Molecular analysis of MHC genes expressed on haplotypes in association with HLA-DR4 reveals that at least six different alleles of the DR beta 1 locus and at least three different alleles of the DQ beta locus occur on different DR4+ haplotypes. Some of these allelic differences are quite substantial, and others are rather subtle, involving as few as two amino acids. The analysis of individual DR and DQ alleles in rheumatoid arthritis identifies some DR4+ genes strongly associated with disease susceptibility and some DR4+ genes which are not. The Dw4(DR4) and Dw14(DR4) DR beta 1 genes appear to represent specific alleles which confer disease risk in RA; other DR beta 1 genes, such as Dw10(DR4), may represent DR beta genes altered during evolution which have lost their contribution to RA susceptibility. DQ beta 3.1(DQw3) and DQ beta 3.2(DQw3) DQ beta genes, which are present on DR4+ haplotypes, represent discrete variable alleles not directly implicated in RA, but which account for HLA-DR4 associations with other diseases, such as the association of DQ beta 3.2(DQw3) with Type I diabetes.