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Amputation of a limb may affect quality of life. However, little is known concerning health-related quality of life in amputees. The purposes of this study were to describe health-related quality of life in a population of lower limb amputees and to investigate potential determinants, including phantom pain. Data from 437 patients with a lower limb amputation were analyzed in this cross-sectional study. Amputation-related problems were investigated using a questionnaire. Health-related quality of life was investigated using the RAND-36 DLV. Amputees with phantom pain had a poorer health-related quality of life than amputees without phantom pain. In general, the most important amputation-specific determinants of health-related quality of life were ‘walking distance’ and ‘stump pain.’