Diffuse large B-cell lymphoma (DLBCL) associated with chronic inflammation is a recently adopted category of DLBCL, which describes an aggressive B-cell lymphoma raised in the setting of non-immune chronic inflammation. Primary presentation of this subtype of DLBCL in bone is extremely rare. Here, we present the case of a 27 year old woman with DLBCL of the right distal femur, identified after a three-year history of chronic osteomyelitis. In this report, we describe the clinical and histopathologic features of this unusual presentation of DLBCL and discuss aspects relevant to diagnosis and treatment of this entity.