OBJECTIVES : To assess disease burden on health-related quality of life (HRQoL) by comparing HRQoL between patients with hereditary transthyretin amyloidosis (hATTR) and a US general population (USGP) sample, and several disease benchmark samples. METHODS : Baseline SF-36v2® Health Survey (SF-36v2) data were collected from 172 adults with hATTR enrolled in the NEURO-TTR trial and compared to the USGP and disease benchmarks: congestive heart failure (CHF), and irritable bowel syndrome (IBS) from the 2009 QualityMetric Norms, and diabetic neuropathy (DN), multiple sclerosis (MS), and Crohn’s disease (CD) from the National Health & Wellness Survey. SF-36v2 scores were adjusted after matching the USGP and disease benchmarks’ age and sex distributions to that of the hATTR sample using regression models and compared using univariate analysis of variance models. Magnitude of sample differences were interpreted using effect sizes (Cohen’s d) and minimal important difference (MID) thresholds established for SF-36v2 subscales and summary scores. RESULTS : Compared with the USGP, hATTR patients scores were considerably worse on all SF-36v2 physical subscales and the physical component summary (PCS; p<0.001). hATTR patients had the greatest deficits in physical functioning and role-physical subscales (ds≥0.74). Group mean differences between hATTR patients and the USGP exceeded the MID thresholds for all SF-36v2 subscales except mental health and mental component summary scores. Relative to patients with gastrointestinal (CD, IBS) and neurological (DN, MS) conditions, hATTR patients had significantly worse physical functioning (all p<0.05 except for MS) and overall physical health as indicated by PCS scores (all p<0.01), while similar physical HRQoL deficits were observed for hATTR relative to patients with CHF. CONCLUSIONS : hATTR patients experienced substantially more HRQoL burden, particularly in physical functioning and other physical health problems, than did the USGP. hATTR patients generally experienced worse physical functioning and overall physical well-being than did patients with CD, IBS, DN, and MS.