Introduction: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease. Currently, numerous genetic loci of SLE have been confirmed. Here we try to further explore additional genes contributing to SLE susceptibility in this study. Methods: Forty nine single nucleotide polymorphisms (SNPs) with moderate-risk for SLE in previous study were genotyped in a large-scale replication study with a total of 3,522 cases and 8,252 controls using the Sequenom Massarray system. Association analyses were performed using logistic regression with gender or sample cohorts as a covariate through PLINK 1.07 software. Results: This replication effort confirmed five reported SLE susceptibility loci reaching genome-wide levels of significance (P-meta < 5.00 x 10(-08)): TNFSF4 (rs1418190, odds ratio (OR) = 0.81, P-meta = 1.08 x 10(-08); rs4916219, OR = 0.80, P-meta = 7.77x 10(-09)), IRF8 (rs2934498, OR = 1.25, P-meta = 4.97 x 10(-09)), miR-146a (rs2431697, OR = 0.69, P-meta = 1.15 x 10(-22)), CD44 (rs2732547, OR = 0.82, P-meta = 1.55 x 10(-11)), and TMEM39A (rs12494314, OR = 0.84, P-meta= 1.01x 10(-09)). Further logistic regression analysis indicated that the genetic effects within TNFSF4 detected in this study are independent from our previously reported signals. Conclusions: This study increases the number of established susceptibility loci for SLE in Han Chinese population and highlights the contribution of multiple variants of modest effect. Although further studies will be required to identify the causal alleles within these loci, the findings make a significant step forward in our understanding of the genetic contribution to SLE in Chinese population.