The serum level of IL-33 was upregulated in systemic lupus erythematosus (SLE), which may be used as biomarkers and/or therapeutic targets for SLE. The aim of this study was to investigate the association of four novel polymorphisms of IL-33 with risk of SLE. The study population comprised 540 Chinese individuals, including 257subjects with SLE and 283 healthy controls. The gene polymorphism was measured using Snapshot SNP genotyping assays and confirmed by sequencing. Serum IL-33 (sIL-33) levels were measured by ELISA. The serum SLE levels were significantly higher in the group of patients with SLE than those in the control group (P < 0.001). The rs1891385C allele was associated with a significantly increased risk of SLE as compared with the rs1891385 A allele (OR = 1.405, 95% CI, 1.052–1.875, P = 0.021). The C-T-T-G haplotype was significantly increased the risk of SLE (OR = 1.411; 95% CI, 1.021–1.948; P = 0.036). IL-33 gene rs1891385 polymorphism was significantly associated with the expression of sIL-33 in the SLE patients. Besides, in our study, we found that the unregulated sIL-33 level was significantly associated with the abnormal changed CRP and ESR. This is the first study reporting the IL-33 gene polymorphisms and SLE, which may help refine the SLE risk profile.