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The purpose of this study was to investigate the incidence of apical periodontitis (AP) in endodontically treated teeth with and without periodontal involvement.The records of 602 patients with 775 root canal–treated teeth were initially examined. Only teeth with adequate root canal filling, adequate coronal restoration, and no AP (periapical index = 1) were selected for further investigation. A total of 194 teeth were included in this cohort study. Age, sex, history of diabetes mellitus, smoking, hypertension, and immunodeficiency disorders were recorded. Two groups were made according to the periodontal status of the patients. The control group included periodontally healthy patients and the periodontal group patients with periodontal disease receiving nonsurgical periodontal treatment. After an observation period of at least 2 years, the incidence of AP was scored using the periapical index. The relationship between patients’ variables and AP was conducted using the Cohen kappa test, the chi-square test, odds ratio (OR), and logistic regression analysis.Newly emerged AP was found in 14% of periodontally involved teeth and in 3% of nonperiodontal involved teeth (P < .05, OR = 5.19, 95% confidence interval). The periodontal condition and hypertension were the only significant factors associated with the presence of AP in the follow-up after univariate logistic regression. Adjusting for hypertension, multivariate logistic regressions showed that periodontal status remained significant (OR = 5.25, 95% CI, P < .05).The risk of developing AP in endodontically treated teeth is 5.19 times higher for patients with periodontal disease compared with patients without periodontal disease.