Background Endodontic treatment planning and treatment success evaluation are largely based on radiographic assessment of anatomical and treatment-related parameters of teeth with apical periodontitis (AP). This prospective clinical study aimed to assess radiographically the 2-year endodontic treatment outcomes for teeth with AP, and to evaluate prognostic validity of Periapical and Endodontic Status Scale (PESS). Methods A total of 128 patients, representing 176 teeth with AP were examined by cone-beam computed tomography at baseline and at 24 months after endodontic treatment. Treatment outcome was evaluated using estimates of periapical radiolucency and the relationship between anatomical structures and location. The strength of the associations between these and treatment-related parameters was tested by logistic regression analysis. PESS sensitivity and specificity were calculated for every treatment risk group (low, moderate, high) of teeth. Results One hundred and fifty-seven teeth, representing 350 root canals had a positive treatment outcome, while 19 teeth, representing 53 root canals had a negative treatment outcome at 24 months. The probability of negative outcome was 25 times higher in the moderate/high-risk group than in the mild-risk group of teeth (OR = 25.1; 95%CI [12.2-51.5]). Pre-treatment complications and retreatment cases with radiolucency were associated with negative outcomes (OR = 35.9; 95%CI [12.6-102.4]; OR = 26.437; 95%CI [10.9-64.1], respectively). PESS sensitivity and specificity was over 80% in all risk groups except for high risk group, due to very low number of cases. Conclusions Endodontic treatment outcome depends on the severity of periapical changes. The presence of complications and retreatment cases with periapical lesions are associated with negative treatment outcome. The PESS is a valid instrument to predict outcome of teeth with low-moderate treatment risk of AP.