The aim of this study was to explore whether the interferon regulatory factor 5 (IRF5) gene rs2070197 polymorphism was associated with systemic lupus erythematosus (SLE) in multiple ethic populations. A meta-analysis was conducted on the C allele of the IRF5 rs2070197 polymorphism. A total of 7 published case-control studies with 12 comparisons involving 8171 SLE patients and 8904 controls were available for this meta-analysis. This meta-analysis demonstrated the IRF5 rs2070197 polymorphism conferred susceptibility to SLE in all subjects (odds ratio (OR) = 2.128, 95 % confidence interval (CI): 1.856-2.441, P < 0.001) without inter-study heterogeneity. The IRF5 rs2070197 polymorphism was identified as risk factors for SLE in Caucasian populations (OR 1.82, 95 % CI 1.70-1.96), but it had no effects (monomorphic) in Asians. Large-scale multicenter epidemiological studies in selected populations with other risk factors were urgently required.