Background <p>Emerging studies have indicated associations between certain viruses (like Epstein-Barr, HIV, and hepatitis viruses) and periodontitis. However, the relationship between Hepatitis A virus (HAV) and periodontitis remains unclear and understood. This study investigated the association between HAV infection and periodontitis in epidemiological and genetic perspective.</p> Methods <p>This study utilized data from the National Health and Nutrition Examination Survey (NHANES 2009-2014) to investigate the potential association between HAV seropositivity and periodontitis. Logistic regression was performed to analyze the cross-sectional relationship between HAV exposure and periodontitis. Then, Mendelian Randomization (MR) analysis was conducted using Genome-Wide Association Study (GWAS) datasets from 23andMe and the Gene Lifestyle Interactions in Dental Endpoints (GLIDE) consortium. Various statistical methods were applied to assess the potential genetic causal relationship between HAV infection and periodontitis.</p> Results <p>The study included 8525 participants, of which approximately 32.15% (3776) had HAV infection and 41.56% (4304) suffered from periodontitis. A positive association was found between HAV infection and periodontitis (OR,1.182; 95%CI, 1.032-1.352). The IVW of MR analysis also suggested a genetic correlation between HAV infection and periodontitis (OR, 1.034; 95%CI, 1.001-1.068). The cross-sectional and MR designs mutually complement each other, enhancing the robustness of the findings.</p> Conclusion <p>This study identified an association between HAV infection and periodontitis, suggesting that HAV may be positively associated with the development of periodontal disease. The results highlight the importance of considering HAV infection in the management and prevention of periodontitis, until this association is validated in prospective and mechanistic studies.</p>