A 19-year-old Appaloosa gelding was reluctant to move. Radiography revealed diffuse, permeative lysis of the cortex and subchondral bone of the phalanges, third metacarpal bones, proximal sesamoid bones, radius, carpal bones, tibia, mandible, and nasal bones of the skull. A comminuted fracture of the distal aspect of the left third metacarpal bone was identified on a lateral to medial radiographic view of the left metacarpophalangeal joint. Histologic examination of the first phalanx, third metacarpal bone, and sternum revealed multifocal infiltrates of nodular lymphosarcoma in cortical and subchondral bone. Osteoclastic cavities were apparent in bone trabeculae contiguous with nodular foci of lymphosarcoma. Osteoclastic osteolysis was not evident at bone surfaces that were not directly adjacent to neoplastic cells. Although lymphosarcoma is the most frequent malignant neoplasia encountered in horses, diffuse neoplastic infiltration of cortical and subchondral bone of the appendicular and axial skeleton represents an unusual presentation of lymphosarcoma.