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Background: Patients who have limb amputation are at risk of chronic pain, including phantom limb pain that can be challenging to treat. The aim of this study was to describe the incidence of pre-operative opioid usage and the incidence and risk factors for new persistent post-operative opioid usage in opioid-naïve patients after limb amputation., Methods: A retrospective study of all patients 18 years and older underwent upper or lower extremity amputations in Landspitali University Hospital between 2005 and 2015. Patients were considered to use opioids pre-operatively if they filled an opioid prescription 1-6 months prior to amputation and were considered to have persistent opioid use if opioid prescriptions were filled between post-operative months four to twenty-four. In addition to incidence estimate, uni- and multivariate analysis was performed to identify risk factors for persistent post-operative opioid usage., Results: Of 328 total patients, 216 (66%) were opioid naïve and 112 (34%) were chronic opioid users. Of the opioid-naïve patients surviving more than 3 months 40 (20%) developed persistent post-operative opioid usage. In multivariate analysis, factors independently associated with persistent post-operative opioid usage were younger age, male gender, pre-operative use of neuropathic medications or benzodiazepines and lower (opposed to upper) extremity amputation., Conclusion: Opioid naïve patients undergoing major amputation had a 20% chance of having a persistent opioid requirement following surgery. This could represent new-onset phantom limb pain or other chronic pain. Our findings should encourage perioperative multimodal efforts to reduce the burden of chronic pain after limb amputations., (© 2019 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)