Diagnosis of bone lesions other than fractures is difficult from radiographs alone because mixed patterns of lysis and bone proliferation are frequently observed. It is important to evaluate whether the lesion is single (monostotic) or involving multiple bones (polyostotic). Correlation of additional information such as the patient signalment, sex, geographic habitat, history, clinical findings, and prior therapy is useful to help establish the most accurate differential diagnosis. The presence of intramedullary lesions with expansile destructive pattern in the metaphyseal region of a middle-aged, large-breed dog is supportive for a diagnosis of a primary bone tumor or an aggressive mycotic osteomyelitis. Serial radiographic studies can be performed to evaluate progression. Rapid bone change tends to occur with neoplasia, whereas slower progression can occur with osteomyelitis. The location of change to the vertebrae, such as spondylitis and diskospondylitis, often helps in the understanding of the underlying disease process. Additional diagnostic procedures, such as biopsies with appropriate lesion sampling and evaluation of serum for fungal titers, should be considered to establish the diagnosis.