Systemic lupus erythematosus (SLE) is an autoimmune disease with unknown etiology, characterized by the presence of auto-antibodies to various cellular components and chronic inflammation of different organ systems. A number of susceptibility loci for SLE have been suggested in different populations, but the nature of the susceptibility genes and mutations is yet to be identified. The programmed cell death 1 gene (PDCD1) was considered to be one of the strongest candidate genes associated with SLE. Here, we analyzed 265 individuals for single-nucleotide polymorphisms (SNPs) in PDCD1, including 122 unrelated individuals affected with SLE and 143 random healthy volunteer individuals in Han Chinese. Genomic DNA was prepared from peripheral blood leukocytes and the SNPs were further confirmed by DNA sequencing. We found there were statistically significant differences in the distribution of genotypes at 7872 locus (OR = 0.59, 95%CI = 0.41-0.85) and 8162 locus (OR = 0.54, 95%CI = 0.37-0.78) between SLE and control. Genotype TT in 7872 locus (OR = 0.58, 95%CI = 0.34-1.00) and GG genotype in 8162 locus (OR = 0.46, 95%CI = 0.26-0.80) might be protective for SLE prevention. The associated SNPs might regulate the binding of some transcription factors, such as AML-1a, USF and MZF-1, suggesting a mechanism through which it can contribute to the predisposition of SLE.