PURPOSE: The aim of this study was to compare the diagnostic accuracy of previously trained endodontists in the detection of artificially created periapical lesions using cone-beam computed tomography (CBCT) and digital periapical radiography (DPR). MATERIALS AND METHODS: An ex vivo model using dry skulls was used, in which simulated apical lesions were created and then progressively enlarged using #1/2, #2, #4, and #6 round burs. A total of 11 teeth were included in the study, and 110 images were obtained with CBCT and with an intraoral digital periapical radiographic sensor (Instrumentarium dental, Tuusula, Finland) initially and after each bur was used. Specificity and sensitivity were calculated. All images were evaluated by 10 previously trained, certified endodontists. Agreement was calculated using the kappa coefficient. The accuracy of each method in detecting apical lesions was calculated using the chi-square test. RESULTS: The kappa coefficient between examiners showed low agreement (range, 0.17-0.64). No statistical difference was found between CBCT and DPR in teeth without apical lesions (P=.15). The accuracy for CBCT was significantly higher than for DPR in all corresponding simulated lesions (P<.001). The correct diagnostic rate for CBCT ranged between 56.9% and 73.6%. The greatest difference between CBCT and DPR was seen in the maxillary teeth (CBCT, 71.4%; DPR, 28.6%; P<.01) and multi-rooted teeth (CBCT, 83.3%; DPR, 33.3%; P<.01). CONCLUSION: CBCT allowed higher accuracy than DPR in detecting simulated lesions for all simulated lesions tested. Endodontists need to be properly trained in interpreting CBCT scans to achieve higher diagnostic accuracy.