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Objective: Relationship between surface antigen differentiation cluster 274 (CD274) gene polymorphism and systemic lupus erythematosus (SLE) risk is limited. This study aims to discuss whether in a Chinese Han population, CD274 gene polymorphisms may relate to SLE susceptibility. Methods: Three hundred and ten SLE patients and 390 healthy controls were included in this case–control study. Using the Kompetitive Allele‐Specific PCR (KASP) approach, five single nucleotide polymorphisms (SNPs), including rs2890658, rs4143815, rs822339, rs2282055, and rs2297137, were genotyped for CD274 gene polymorphisms. Correlation between the polymorphisms and clinical, laboratory features in SLE patients were discussed. Results: Frequency of C allele was substantially lower in SLE patients than in healthy controls (p =.015), and CC genotype was significantly negatively related to developing SLE at locus rs4143815 (p =.013). At locus rs822339, frequency of GA genotype was higher than that of the healthy controls (p =.006). At locus rs2282055, frequency of GG genotype was lower than that of healthy controls (p =.024). According to subgroup analysis, the CD274 gene polymorphisms rs2890658, rs4143815, rs822339, rs2282055, and rs2297137 were partly linked to some clinical symptoms of SLE patients, such as Complement 4 (C4), C‐reactive protein (CRP), and erythrocyte sedimentation rate (ESR). Conclusion: CD274 gene polymorphisms may be susceptible to SLE in the Chinese Han people. [ABSTRACT FROM AUTHOR]