A missence single-nucleotide polymorphism (SNP) in the protein tyrosine phosphatase nonreceptor 22 (PTPN22) gene known as R620W (rs2476601) was recently reported to be associated with several autoimmune diseases including Graves' disease (GD). The association was repeatedly confirmed in the populations of North European ancestry. However, this amino acid was reported to be nonpolymorphic in the Asian populations. Since the gene confers an impact on autoimmune diseases, we attempt to explore an association between the PTPN22 gene and autoimmune thyroid disease (AITD) in a Japanese population without restricting to rs2476601. Previous investigations have also demonstrated that two intronic SNPs (rs706778 and rs3118470) in the interleukin-2 receptor-alpha (IL2RA) gene were associated with type 1 diabetes in the Japanese population.We genotyped the five SNPs (rs12760457, rs2797415, rs1310182, rs2476599, and rs3789604) of the PTPN22 and the two SNPs (rs706778 and rs3118470 in the IL2RA gene) in 456 Japanese patients with AITD (286 with GD, 170 with Hashimoto's thyroiditis) and 221 matched Japanese control subjects. Seven SNPs were analyzed by either the SNAPshot method or the high-resolution melting and unlabeled probe methods. Case-control association studies were performed using the chi(2) and Fisher's exact tests with Yates correction. Haplotype was conducted using the expectation-maximization algorithm.No association was found between any of the individual SNPs of the PTPN22 gene and AITD. Permutation analysis revealed that the distribution of one haplotype is significantly different between patients with AITD and controls (p = 0.0036). A novel protective effect of a haplotype containing five SNPs was observed (p < 0.0001 for AITD, p < 0.0001 for GD, and p < 0.0001 for Hashimoto's thyroiditis, respectively). The GG allele of rs3118470 in the IL2RA gene was significantly associated with GD (p = 0.03), although the association was weak.Significant difference in the distribution of the haplotype suggests that the PTPN22 gene rather than rs2476601 is involved in the development of AITD in the Japanese population.