Purpose: To report a rare presentation of an ameloblastoma mimicking an endo-periodontal lesion. Materials and methods: In this case report, we present the unusual clinical course of a 78-year-old Caucasian male patient, seeking single tooth implant rehabilitation at location 42 (lower right lateral incisor), initially unsuccessfully treated at different clinics for a persistent endo-periodontal lesion associated with this tooth, by both an endodontist and a periodontologist, which finally lead to tooth loss. Results: CBCT imaging of the anterior mandible region revealed a persistent radiolucency and subsequent enucleation of the lesion in the partially healed extraction socket revealed the true underlying diagnosis: a solid follicular ameloblastoma. A re-entry with biopsy was planned after radiological confirmation of lesion growth 1 year later, reconfirming the diagnosis and necessitating partial segment resection of the mandible. Conclusions: In the presence of lesions refractory to therapy, consideration towards a broader differential diagnosis and an appropriate investigation should be undertaken before the decision on implant placement. Keywords: ameloblastoma, cone beam computed tomography, dental implant, mandible, periapical lesion, periodontal defect