A case of a 45-year-old white man admitted for an osteomyelitis and subsequently diagnosed affected by an IE stage, diffuse high grade large B cell non-Hodgkin's lymphoma of the mandible is reported. The patient presented a swelling in the right mandibular region with paraesthesia of the ipsilateral lower lip without nodal involvement of the neck. After an incisional biopsy, which showed a diffuse high grade large B-cell non-Hodgkin's lymphoma, the patient was staged and treated with CEOP protocol for six courses and subsequently external beam radiation therapy with complete remission of the lesion.