A 57-year-old woman was admitted with swelling of the femur. MRI showed that an intramedullary lesion had expanded from the trunk to the distal portion where it had formed an extramedullary tumor mass. An open biopsy showed diffuse proliferation of abnormal lymphoid cells. Immunohistochemical staining and flow cytometry demonstrated LCA+, CD3-, CD23-, CD79a+, CD5+, IgM+, IgD- and kappa + and cyclin D1-. FISH analysis did not detect t(11;14)(q13;q32). The final diagnosis was de novo CD5+ diffuse large B-cell lymphoma (DLBL) of the bone at clinical stage IEA. The patient suffered a pathological fracture in the femur after two courses of CHOP. The therapy was changed to ESHAP and irradiation. The result was assessed as a complete remission (CR). One month later, the patient presented with epigastric pain. MRI showed the tumor at the spleen and kidney and hydronephrosis due to pelvic lymphadenopathy, but did not show a tumor in the femur. An open biopsy of the pelvic lymph node showed relapse. The tumor and hydronephrosis disappeared and necrosis in the kidney was observed on MRI after ESHAP. De novo CD5+ DLBL appears to constitute a unique subset of DLBL with an aggressive clinical course and requires established therapeutic strategies.