ObjectivePeriodontal disease may increase the risk of cardiovascular disease(CVD). Periodontal inflammation can contribute to CVD through both local and systemic inflammatory pathways. The Periodontal Inflamed Surface Area (PISA) quantifies the extent of periodontal inflammation; however, evidence based on large, representative populations remains limited. This study aimed to evaluate the association between PISA and CVD using data from the National Health and Nutrition Examination Survey (NHANES). MethodsThis study utilized data from six cycles of NHANES, including a total of 8 925 participants. Three machine learning algorithms—Random Forest, XGBoost, and Boruta—were used for key feature selection. A logistic regression model was constructed to assess the association between PISA and CVD prevalence, and further machine learning prediction models were developed to explore the additional predictive value of PISA in identifying CVD status. ResultsParticipants in the highest quartile of PISA showed a higher prevalence of CVD. Multivariable logistic regression analysis and restricted cubic spline analysis demonstrated that PISA score was positively associated with CVD in a linear fashion (OR=2.85, 95%CI 1.75 to 4.62, P<0.001). ConclusionIn individuals with periodontitis, the PISA index is linearly associated with the prevalence of cardiovascular disease events and their subtypes. As a continuous measure of periodontal inflammatory burden, PISA may help identify people at higher risk of CVD.