INTRODUCTION: Periodontitis is a host-mediated oral disease caused by multifactorial microbes. Previous studies suggested that interleukin-6 (IL-6) gene promoter polymorphisms (-174G>C) are associated with the risk of periodontitis, although the results were inconclusive. This study investigated the association between IL-6 -174G>C polymorphism and susceptibility to periodontitis. METHOD: A comprehensive search was conducted in PubMed, EMBASE, Web of Science, and Google Scholar databases to retrieve relevant studies. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of the association between 174G>C polymorphism and the risk of periodontitis. Cochrane Q and I2 statistics were used to measure heterogeneity between studies. Publication bias was estimated using Begg's funnel plots and Egger's test. RESULTS: Our results showed significant differences in the allelic (C vs. G: OR = 0.82, CI = 0.65-1.03), recessive (CC vs. GC+GG: OR = 0.69, CI = 0.42- 1.13), and dominant (GC+CC vs. GG: OR = 0.85, CI = 0.63-1.13) genetic models of the IL6 -174G>C polymorphism and risk of periodontitis. Furthermore, subgroup analysis showed decreased susceptibility to periodontitis associated with IL6 -174 G>C in a Brazilian population (C vs. G: OR = 0.60, CI = 0.41- 0.88; GC+CC vs. GG: OR = 0.57, CI = 0.42- 0.78) but not in Asian or Caucasian populations. CONCLUSION: The findings of this study revealed that the IL6 -174 "C" allele is protective against periodontitis in the Brazilian population.