There is conflicting literature on the effect of post-amputation pain on quality of life (QOL) and no available literature on the relationship of pain medications to QOL of amputees in pain. The aims of the study were to compare QOL in lower limb amputees with significant pain to those with minimal pain and compare QOL in amputees on multiple pain medications (≥3 and/or ≥ 40 mg morphine equivalent/day) to those on minimal. Cross-sectional study of amputees (n = 101) utilizing standardized (brief pain inventory, pain self-efficacy, Euro QOL scale), institutional amputee specific questionnaires. Post-amputation pain was common (69%), but only 13% of the participants were using more pain medications. High-pain interference and poor self-efficacy were associated with poorer QOL after adjusting for age, gender and cause of amputation. High medication use was associated with high-pain interference and poor self-efficacy, but there was minimal correlation between pain scores and medication usage (p > 0.05). Quality of life was not influenced by high medication usage (p > 0.05 for pain interference; p > 0.05 for self-efficacy). Post-amputation pain continues to be a major determinant of QOL in lower limb amputees, but the role of pain medications on an amputee's QOL remains unclear.IMPLICATIONS FOR REHABILITATIONAn amputee's QOL is affected by the severity of their post-amputation pain even beyond six months post their amputation.An amputee with more pain may not necessarily take more pain medications to manage their pain. The amount of pain medications taken may not influence their self-reported QOL.Pain and QOL assessment should be integrated into routine clinical evaluation of adult amputees. Standardized screening tools and/or formative assessment can be utilized for assessing QOL.