Radiation-induced peripheral neuropathy is most extensively studied for brachial plexus. Stoll and Andrews' first report of radiation-induced brachial plexopathy in 1966 challenged the long-held notion that adult nervous tissue is radioresistant.1 Since then, it has been recognized that radiation-induced peripheral neuropathy can result from brachytherapy, intraoperative radiation, and high-dose external beam radiotherapy (EBRT) in the treatment of extremity soft-tissue sarcomas, tumors in the retroperitoneum, pelvis and inguinal region, or paraspinal soft tissue or bone sarcomas around the cauda equinae. Extensive experimental and clinical studies of intraoperative radiotherapy (IORT) suggest that 20 Gy is the tolerance dose for single fraction IORT.2,3,4,5,6,7,8,9–10 Emami et al.11 estimated the TD 5/5 for peripheral neuropathy to be 60 Gy and a TD 50/5 of 75 Gy in standard fractionation when the entire cauda was irradiated. This chapter describes the relevant anatomy of peripheral nerves as well as pathophysiology of radiation-induced peripheral neuropathy and plexopathy other than the brachial plexus, which is addressed in Chapter 23. We describe the clinical presentation, differential diagnoses, workup, risk factors, and treatment of radiation-induced peripheral neuropathy. We draw on experience from intraoperative radiation for retroperitoneal or pelvic tumors, high-dose external beam radiation for lumbosacral spine sarcomas, and external beam/brachytherapy for extremity sarcomas.