Purpose: The purpose of this study was to analyze the reliability of 7 panoramic radiographic signs for predicting proximity of the root apices of mandibular third molars to the mandibular canal using cone-beam computed tomography and to correlate these findings with the Pell and Gregory and the Winter classification systems. Materials and Methods: An observational, cross-sectional, descriptive study was conducted on 74 patients with bilateral impacted mandibular third molars. Four panoramic radiographic signs were observed in the tooth root (darkening, deflection, and narrowing of the root apices, and bifid apices), and another 3 in the mandibular canal (diversion, narrowing, and interruption of the mandibular canal). Cone-beam computed tomography images were analyzed to identify disruption and diversion of the mandibular canal and root deflection. Results: Binary logistic regression showed that only 4 of the 7 panoramic radiographic signs were able to predict proximity of the root apices of the mandibular third molars to the mandibular canal: darkening of the root, deflection of the root, narrowing of the root, and interruption of the mandibular canal (P<0.05). Conclusion Darkening, deflection, and narrowing of the root, in tandem with the interruption of the mandibular canal on panoramic radiographs, indicate that cone-beam computed tomography should be performed when planning the extraction of impacted mandibular third molars. Proximity between mandibular third molars and the mandibular canal is correlated with the Winter classification.