The aim of this study was to examine the association of single-nucleotide polymorphisms (SNPs) in IL-21 gene with susceptibility to systemic lupus erythematosus (SLE) in a Chinese population. A total of 605 independent SLE patients and 666 unrelated healthy controls were recruited for the case-control association study. Two SNPs (rs2221903 and rs907715) within the IL-21 gene intronic region were genotyped by TaqMan SNP allelic discrimination methods. The allele T frequency of SNP rs2221903 in patients and healthy controls was 89.4 % and 86.8 %, respectively [T versus C, odds ratio (OR) = 1.287, 95 % confidence interval (CI) = 1.010-1.640]. No significant differences in genotype frequencies were shown between SLE patients and healthy controls (P value = 0.705, 0.406, respectively). However, the effect of recessive model (TT versus CC + CT, OR = 1.368, 95 % CI = 1.050-1.781) was observed. Distributions of allele and genotype frequencies of the SNP rs907715 showed no significant differences between SLE patients and controls. Analysis of the haplotypes revealed that CC haplotype was significantly associated with SLE (OR = 0.734, 95 % CI = 0.573-0.941). In conclusion, our findings suggest that a SNP (rs2221903) and CC haplotype (rs2221903 and rs907715) of the IL-21 gene is associated with SLE in the Chinese population. However, further studies are needed to determine the functional consequences of this polymorphism with SLE susceptibility.