Background: Systemic lupus erythematosus (SLE) is an autoimmune disease under genetic control. Growing evidences support the genetic predisposition of HLA?DRB1 gene polymorphisms 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 (HLA?DR3 and HLA?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, HLA?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％ CI: 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.