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The failure of immunological tolerance to self‐antigens plays a fundamental role in the pathogenesis of systemic lupus erythematosus (SLE). PD‐1 is an inhibitory receptor for regulating the immune system and preventing development of autoimmune disorders. This study aimed to determine the role of four single‐nucleotide polymorphisms (SNPs) within programmed cell death 1 (PDCD1 or PD‐1) gene and haplotypes defined by these SNPs in susceptibility to SLE in the Iranian population. Blood samples were obtained from 253 SLE and 564 healthy subjects. Red blood cells were lysed and genomic DNAs were extracted using salting‐out method. Genotype determinations of PD1.1, PD1.3, PD1.5 and PD1.9 SNPs were performed by polymerase chain reaction–restriction fragment length polymorphism (PCR‐RFLP), and 12 haplotypes were constructed by PDCD1 SNPs. Our results showed significant differences in PD1.5 genotype frequencies between patient and control groups (p <.001). The frequencies of PD1.5 C/C, C/T and T/T genotypes versus other genotypes in SLE patients significantly differed from healthy subjects (p <.001, p =.001 and p =.002, respectively). Allelic analysis indicated a significant association between the frequency of PD1.5C allele and development of SLE in our population (odds ratio [OR] = 1.91, 95% confidence interval [CI] = 1.51–2.42, p <.001). At the haplotype level, GGCC, GACT and GGCT haplotypes were significantly different between SLE and control groups (OR = 2.14, 95% CI = 1.73–2.66, p <.001; OR = 9.76, 95% CI = 4.47–21.3, p <.001; and OR = 0.32, 95% CI = 0.24–0.42, p <.001, respectively). Based on these findings, PD1.5 SNP and some haplotypes of PDCD1 contribute to SLE risk in the Iranian population. [ABSTRACT FROM AUTHOR]