This case report describes the endodontic treatment of a large apical periodontitis with well-defined margins adjacent to teeth #22-24. After the initial endodontic treatment, continued expansion of the mandible cortical bone was observed, indicating a need to surgically enucleate the lesion and submit it for histopathologic examination. The microscopic examination indicated a diagnosis of ameloblastoma. Ameloblastoma is a benign epithelial neoplasm of odontogenic origin, and depending on the stage of development, it can mimic a periapical lesion and therefore should be considered in establishing an endodontic differential diagnosis. The definitive diagnosis for some periapical lesions can only be made by a histopathologic examination.