Purpose: The aim of this in vitro study was to determine the sensitivity and specificity of cone-beam computed tomography (CBCT) and digital periapical radiography in the detection of mesial root perforations of mandibular molars. Materials and Methods: In this in vitro study, 48 mandibular molars were divided into 4 groups. First, the mesial canals of all the 48 teeth were endodontically prepared. In 2 groups (24 teeth each), the roots were axially perforated in the mesiolingual canal 1-3 mm below the furcation region, penetrating the root surface ("root perforation"). Then, in one of these 2 groups, the mesial canals were filled with gutta-percha and AH26 sealer. Mesial canals in one of the other 2 groups without perforation (control groups) were filled with the same materials. The CBCT and periapical radiographs with 3 different angulations were evaluated by 2 oral and maxillofacial radiologists. The specificity and sensitivity of the two methods were calculated, and P<0.05 was considered significant. Results: The sensitivity and specificity of CBCT scans in the detection of obturated root canal perforations were 79% and 96%, respectively, and in the case of three-angled periapical radiographs, they were 92% and 100%, respectively. In non-obturated root canals, the sensitivity and specificity of CBCT scans in perforation detection were 92% and 100%, respectively, and for three-angled periapical radiographs, they were 50% and 96%, respectively. Conclusion: For perforation detection in filled-root canals, periapical radiography with three different horizontal angulations would be trustworthy, but it is recommended that CBCT be used for perforation detection before obturating root canals.