Objective The aim of this study is to determine whether the functional interferon regulatory factor 5 ( IRF5) polymorphism rs2004640 is associated with susceptibility to systemic lupus erythematosus (SLE) in multiple ethnic populations. Methods A meta-analysis was conducted on the T allele of the IRF5 rs2004640 polymorphism in all study participants as well as each ethnic population. Results Twenty research articles that included 28 comparative studies of 20,892 patients and 24,930 controls were included in the meta-analysis. The Asian population had a much lower prevalence of the T allele than any other study population at 28%, and the European population had the highest prevalence of the T allele at 52%. Meta-analysis showed an association between the IRF5 rs2004640 polymorphism and SLE in all participants (odds ratio = 1.472, 95% confidence interval = 1.370–1.582, p < 0.001). Analysis after stratification by ethnicity indicated that the IRF5 rs2004640 T allele is significantly associated with SLE in Europeans, Asians, Latin Americans and Arabs. Conclusions This meta-analysis confirms that the IRF5 rs2004640 polymorphism is associated with SLE susceptibility in different ethnic groups, and that its prevalence is ethnicity dependent.