Background: Light chain (AL) amyloidosis is a rare disease characterized by misfolded amyloid protein deposits in tissues and vital organs, and little is known about the burden of AL amyloidosis on health-related quality of life. This study aimed to quantify the burden of AL amyloidosis in terms of health-related quality of life in a diverse, community-based sample of AL amyloidosis patients.Results: The SF-36v2® Health Survey (SF-36v2), a widely used generic measure of health-related quality of life (using physical and mental summary scales and subscales assessing eight aspects of functioning and well-being), was administered as an online survey of AL amyloidosis patients with AL amyloidosis (ClinicalTrials.gov, NCT02574676 ; n = 341). Compared with adjusted general population sample norms, health-related quality of life of AL amyloidosis patients was significantly worse across all SF-36v2 scales and summary measures based on analysis of variance (p < 0.05 for all). The largest decrement in AL amyloidosis patients was related to General Health (Δ = 9.7; p < 0.001). With the exception of Bodily Pain and Mental Health, differences were also clinically meaningful based on established clinically minimal important differences. The burden of AL amyloidosis overall and in key subgroups tended to be greater on physical health than on mental health. Stratified analyses indicated additional burden among patients with recently diagnosed disease and those with cardiac involvement than among their respective counterparts.Conclusion: Understanding the burden of AL amyloidosis highlights the unmet need for treatment, helps physicians identify ancillary treatments and services geared towards improving patients' functioning, well-being, and overall health-related quality of life. These findings also help to support the use of health-related quality of life end points as important outcome measures in current and future treatment studies.Trial Registration: ClinicalTrials.gov, NCT02574676 . Registered October 5, 2015. [ABSTRACT FROM AUTHOR]