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Oral manifestation of diffuse large B-cell lymphoma (DLBCL) usually represents late involvement of disseminated and advanced disease. In this case, the oral lesion was the first sign of the disease. A 66-year-old male patient complained of difficulty adapting the upper total prosthesis for the last month. No underlying diseases have been reported except recent fatigue and weight loss complaint. Physical examination revealed a submucosal tumor in the maxillary region, which was 4 cm, exophytic, painless, and of fibrous consistency, and mucosa of recoating with areas of ulceration. Computed tomography showed an infiltrative, unilocular, isodense, expansive lesion with maxillary bone alteration as well as multiple bilateral supra and infradiaphragmatic lymphadenopathy. An incisional biopsy of the lesion was performed, and the morphologic profile associated with the immunohistochemical profile favored the diagnosis of DLBCL. The patient was submitted to the rituximab, cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (Oncovin), and prednisone regimen associated with intrathecal chemotherapy with complete remission of the oral lesion.