Significance The role of the MHC region has been a long-standing issue in chronic inflammatory diseases, such as rheumatoid arthritis, and it has not been possible to identify the underlying specific polymorphism. Here, we provide evidence that some of the MHC association must be explained by how closely linked genes operate together as haplotype blocks. We identified a conserved haplotype, Ltab-Ncr3, comprising five genes ( lymphotoxin α and β, Tnf , leukocyte-specific transcript 1 , and natural cytotoxicity-triggering receptor 3 ) within MHC class III, regulating arthritis. We found significant coexpression of the Ltab-Ncr3 genes, indicating how these genes may work together as a haplotype. Furthermore, haplotype-specific differences in Ltab-Ncr3 gene expression and alternative splicing correlate remarkably to susceptibility to arthritis. Our data show that a conserved haplotype within MHC class III regulates arthritis development.