Objective. Analyses of families with rheumatoid arthritis (RA) have suggested the presence of a putative susceptibility locus on chromosome 14q21-23. This large population-based genetic association study was undertaken to examine this region.Methods. A 2-stage case-control association study of 950 unrelated Japanese patients with RA and 950 healthy controls was performed using >400 genebased common single-nucleotide polymorphisms (SNPs).Results. Multiple SNPs in the PRKCH gene encoding the isozyme of protein kinase C (PKC) showed significant single-locus disease associations, the most significant being SNP c.427؉8134C>T (odds ratio 0.72, 95% confidence interval 0.62-0.83, P ؍ 5.9 ؋ 10 ؊5 ). Each RA-associated SNP was consistently mapped to 3 distinct regions of strong linkage disequilibrium (i.e., linkage disequilibrium or haplotype blocks) in the PRKCH gene locus, suggesting that multiple causal variants influence disease susceptibility. Significant SNPs included a novel common missense polymorphism of the PRKCH gene, V374I (rs2230500), which lies within the ATP-binding site that is highly conserved among PKC superfamily members. In circulating lymphocytes, PRKCH messenger RNA was expressed at higher levels in resting T cells (CD4؉ or CD8؉) than in B cells (CD19؉) or monocytes (CD14؉) and was significantly down-regulated through immune responses.Conclusion. Our results provide evidence of the involvement of PRKCH as a susceptibility gene for RA in the Japanese population. Dysregulation of PKC signal transduction pathway(s) may confer increased risk of RA through aberrant T cell-mediated autoimmune responses.