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AIM This study sought to investigate associations of 25(OH)D metabolites with periodontitis, and to assess causality using Mendelian randomization (MR). METHODS This study included 7,246 participants of the National Health and Nutrition Examination Survey, 2009-2012. The association of periodontitis with 25(OH)D metabolites was assessed using multivariable logistic regression analysis. 2-sample MR for 25(OH)D, 25(OH)D3 , and C3-epi-25(OH)D3 with periodontitis (n = 17,353 cases/28,210 controls) was conducted. The principal analysis was inverse-variance-weighted approach. We controlled for horizontal pleiotropy using five additional methods. RESULTS Based on the observational study, each 1-point increase in standard deviation of 25(OH)D lowered the risk of periodontitis by 15% (OR = 0.85, 95% CI: 0.78-0.93, P = 0.006) after multivariable adjustment. A similar relationship was observed between 25(OH)D3 and periodontitis (OR = 0.88, 95% CI: 0.80-0.97, P = 0.031). Furthermore, a potential nonlinear association was found between periodontitis with both 25(OH)D and 25(OH)D3 . However, C3-epi-25(OH)D3 was not found to be associated with periodontitis risk. IVW-MR showed that periodontitis risk was not significantly associated with genetically increased levels of 25(OH)D (OR = 1.02, 95% CI: 0.90-1.16, P = 0.732), 25(OH)D3 (OR = 1.04, 95% CI: 0.93-1.17, P = 0.472), and C3-epi-25(OH)D3 (OR = 1.11, 95% CI: 0.87-1.41, P = 0.400). The pleiotropy-robust MR approaches yielded similar results after we had eliminated the variants with horizontal pleiotropy risk. CONCLUSION Cross-sectional observational analysis identified significant relationships between periodontitis with 25(OH)D metabolites, while findings based on MR study do not support a causal role. This article is protected by copyright. All rights reserved.