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Metastatic bone disease is the most common cause of destructive bone lesions in adults, and involvement of the humerus is common. Patients with destructive lesions involving <50% of the cortex are treated nonsurgically with external beam irradiation. Patients with diaphyseal lesions involving ≥50% of the cortex or those with pain after irradiation can be treated with intramedullary nailing to achieve rigid fixation. Although closed intramedullary nailing is used most often, open nailing with methylmethacrylate is appropriate for destructive lesions in which rigid fixation cannot be achieved with closed nailing. Plate fixation is acceptable when adequate proximal and distal cortical bone is present for screw purchase, although proximal humeral lesions usually are treated with prosthetic arthroplasty. Postoperative external beam irradiation can help prevent disease progression and subsequent loss of fixation. However, when disease progression persists or rigid internal fixation is not feasible because of extensive bone destruction, wide resection and reconstruction with a custom prosthesis can be done.