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A significant proportion of patients report long-term pain that is ≥5 on a 0-10 intensity scale after limb-sparing surgery for malignancies of the long bones. Patients experience several distinct types of pain after limb-sparing surgery which constitute a complex clinical entity. This retrospective study examined 26 years of experience in a pediatric institution (1981-2007) in pain management as long as 6 months after limb-sparing surgery and reviewed the historical evolution of pain interventions. One hundred fifty patients underwent 151 limb-salvage surgeries for bone cancer of the extremities in this series. Pain treatment increased progressively in complexity. Therapies included opioids, nonsteroidal antiinflammatory drugs, acetaminophen-opioid combinations, postoperative continuous epidural infusion, anticonvulsants and tricyclic antidepressants for neuropathic pain, local anesthetic wound catheters, and continuous peripheral nerve block catheters. Management of pain after limb-sparing surgery has evolved over the 26 years of this review. It currently relies on multiple “layers” of pharmacologic and nonpharmacologic strategies to address the complex mixed nociceptive and neuropathic mechanisms of pain in this patient population.