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Background: Pre-operative radiographic assessment of the anatomical relationship between the roots of the mandibular third molar and the inferior alveolar nerve (IAN) is a must to minimize the risk of IAN injury during surgery. Objectives: To compare the radiographic signs of digital orthopantomogram (OPG) and cone-beam computed tomography (CBCT). An additional objective was to assess the cortex status between the mandibular canal and third molar on CBCT images in relation to the demographic characteristics, region (right or left side), and angulation of mandibular molar. Methodology: In this retrospective study, a total of 350 impacted mandibular third molars with a close relationship between the inferior alveolar canal (IAC) and impacted mandibular third molars on digital OPG were further referred for CBCT imaging for assessment of the position of the mandibular canal. The study was conducted between August 2018 and February 2020. Digital OPGs were evaluated for radiographic signs like interruption of the mandibular canal wall, darkening of the roots, diversion of the mandibular canal, and narrowing of the mandibular canal. The age and sex of patients, site of impacted third molar, Winter's classification of mandibular third molar, position of IAC relative to impacted molar, and the radiographic markers of OPG were assessed for cortical integrity using CBCT. Chi square testing was applied to study the values of difference and binomial logistic regression was done to assess the factors associated with cortication. Statistical significance was set at p ≤ 0.05. Results: Among 350 patients, 207 (59.1%) were male and 143 (40.9%) were female with a mean age of 36.8 years. The most common OPG sign was interruption of white line, seen in 179 (51.1%) cases. In total, 246 cases (70.3%) showed an absence of canal cortication between the mandibular canal and the impacted third molar on CBCT images. Cortication was observed in all cases with a combination of panoramic signs which was statistically significant (p = 0.047). Cortication was observed in 85 (50.6%) cases where IAC was positioned on the buccal side, 11 (16.9%) in cases of inferiorly positioned IAC, and just 8 (7.6%) for cases of lingually positioned IAC which was statistically significant (p = 0.003). Statistically insignificant (p > 0.05) results were noted for cortex status in CBCT images with regards to the age, sex, site, and angulation of impacted third molars. Conclusion: CBCT imaging is highly recommended for those cases where diversion of the mandibular canal is observed on OPG and when the roots are present between canals. [ABSTRACT FROM AUTHOR]