Background: Systemic lupus erythematosus (SLE) is an autoimmune disease under genetic control. Growing evidences support the genetic predisposition of HLA-DRB1 gene polytnorphisms to SLE, yet the results are not often reproducible. The purpose of this study was to assess the association of two polymorphisms of HLA-DRB1 gene (LILA-DR3 and LILA-DR15) with the risk of SLE via a comprehensive meta-analysis. Methods: This study complied with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Case-control studies on HLA-DRB1 and SLE were searched from PubMed, Elsevier Science, Springer Link, Medline, and Cochrane Library database as of June 2018. Analysis was based on the random-effects model using STATA software version 14.0. Results: A total of 23 studies were retained for analysis, including 5261 cases and 9838 controls. Overall analysis revealed that HLA-DR3 and HLA-DR15 polymorphisms were associated with the significant risk of SLE (odds ratio [OR]: 1.60, 95% confidence interval (CI): 1.316-1.934, P = 0.129 and OR: 1.68,95% CI: 1.334-2.112, P = 0.001, respectively). Subgroup analyses demonstrated that for both HLA-DR3 and HLA-DR15 polymorphisms, ethnicity was a possible source of heterogeneity. Specifically, LILA-DR3 polymorphism was not associated with SLE in White populations (OR: 1.60, 95% CI: 1.320-1.960, P= 0.522) and HLA-DR15 polymorphism in East Asian populations (OR: 1.65, 95% CI: 1.248-2.173, P = 0.001). In addition, source of control was another possible source for both HLA-DR3 and HLA-DR15 polymorphisms, with observable significance for HLA-DR3 in only population-based studies (OR: 1.65, 95% CI: 1.370-1.990, P = 0.244) and for HLA-DR15 in both population-based and hospital-based studies (OR: 1.38, 95% CI: 1.078-1.760, P = 0.123 and OR: 2.08, 95% CL 1.738-2.490, P = 0.881, respectively). Conclusions: HLA-DRB1 gene may be a SLE-susceptibility gene, and it shows evident ethnic heterogeneity. Further prospective validations across multiple ethnical groups are warranted.