Objective.We investigated potential associations between rheumatoid arthritis (RA) and interferon regulatory factor 5 (IRF5) polymorphisms in a metaanalysis.Methods.This metaanalysis included 5 case-control studies, which provided a total of 6582 RA cases and 5375 controls. Odds ratios (OR) were employed to evaluate the risk of RA according to the 4 single-nucleotide polymorphisms (SNP) inIRF5(rs729302, rs2004640, rs752637, and rs2280714) and data were analyzed in respect to association between alleles.Results.Among 4 candidate SNP, rs729302, rs2004640, and rs2280714 were statistically significant; both allele C of rs729302 and allele G of rs2004640 within the promoter region ofIRF5were associated with a protective effect [random-effects (RE) OR 0.889, 95% confidence interval (CI) 0.803–0.977, p = 0.015 for rs729302; and RE OR 0.905, 95% CI 0.848–0.965, p = 0.002 for rs2004640]. Similar results were also obtained in T allele of rs2280714 in the 3’-untranslated region (RE OR 0.927, 95% CI 0.866–0.992, p = 0.029). There was no evidence of publication bias from funnel-plot asymmetry and Egger’s regression test.Conclusion.Our metaanalysis supported the evidence of the significant role ofIRF5polymorphisms in RA.