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CD247 and CD226 play important roles in signaling of lymphocytes. Single nucleotide polymorphisms (SNPs) of genes encoding CD247 and CD226 have been associated with the risk of several autoimmune disorders. This study aimed to evaluate the possible association between CD226 and CD247 genes SNPs and risk of systemic sclerosis (SSc) in Iranian population. Study participants were 455 SSc patients and 455 age, sex and ethnic-matched healthy individuals. Genotyping of rs2056626 and rs763361 at CD247 and CD226 genes, respectively, was carried out using TaqMan MGB-based allelic discrimination real-time PCR. Neither alleles nor genotypes of both SNPs showed significant association with the risk of SSc. Furthermore, association analysis of the genotypes with clinical manifestations of the disease revealed that rs763361 variants were associated with the forced vital capacity (FVC) in SSc patients. Our results suggest that genetic variants of CD226 and CD247 genes may not be a contributing factor in pathogenesis of SSc in Iranian population.