Background: Neurological involvement is a serious complication associated to the surgical removal of impacted mandibular third molars and the radiological investigation is the first mandatory step to assess the risk of a possible post-operative injury to the inferior alveolar nerve (IAN). The aim of this study was to introduce a new radiological classification that could be normally used in clinical practice to assess the relationship between an impacted third molar and mandibular canal on cone beam CT (CBCT) images. Material and Methods: CBCT images of 80 patients (133 mandibular third molars) were independently studied by three members of the surgical team to draw a classification that could describe all the possible relationships between third molar and IAN on the cross-sectional images. Subsequently, the study population was subdivided according to this classification. The SPSS software, version 15.0 (SPSS® Inc., Chicago, Illinois, USA) was used for the statistical analysis. Results: Eight different classes were proposed (classes 0-7) and six of them (classes 1-6) were subdivided in two subtypes (subtypes A-B). The distribution of classes showed a prevalence of buccal or apical course of the mandibular canal followed by lingual position and inter-radicular one. No differences have resulted in terms of anatomic relationship between males and females apart from a higher risk of real contact without corticalization of the canal when the IAN had a lingual course for female group. Younger patients showed an increased rate of direct contact with a reduced calibre of the canal and/or without corticalization. Conclusions: The use of this classification could be a valid support in clinical practice to obtain a common language among operators in order to define the possible relationships between an impacted third molar and the mandibular canal on CBCT images