OBJECTIVES: TTR amyloidosis, a progressive, degenerative ultra-rare genetic disease, can cause familial amyloid polyneuropathy (TTR-FAP) and cardiomyopathy (TTR-CM), requiring substantial caregiver support.  This study evaluated the burden of illness on patients’ and caregivers’ work productivity, healthcare resource use (HCRU), and health-related quality of life (HRQoL). METHODS: An online survey including the Work Productivity & Activity Impairment (WPAI) questionnaire, EQ-5D, & HCRU questions recruited TTR-FAP and TTR-CM patients and caregivers through two U.S.-based patient advocacy groups.   RESULTS: Thirty-three TTR patients (26 males) and 18 caregivers (7 males) completed the survey. Most were aged over 60; mean disease duration was approximately 6 years (patients) or 5 years (caregivers with disease). Most patients and caregivers had a college degree.  Generally caregivers (77.8%) were the primary caregiver for their patient; 61.1% also had amyloidosis. Unemployment was high in patients with TTR-FAP (42.9%), TTR-CM (60.0%), both TTR-FAP/CM (71.4%); only 33.3% of caregivers reported working part/full-time. Employment was highest for TTR-FAP patients (n=10), yet 11.8% missed work, 32.2% were impaired at work and 38.5% reported overall work impairment due to TTR. Liver transplant, the primary treatment option, occurred in 42.4% patients and 18.2% caregivers with disease.  A majority of patients reported outpatient visits to healthcare providers in the past 3 months for disease: 85.7% TTR-FAP, 100% TTR-CM, and 85.7% for TTR-FAP/CM. Hospitalization rates ranged from 14.3-30.0% across all patient groups, with 14.3-23.8% for emergency visits. EQ-5D Index scores for patients were 0.80 (SD=0.14) with transplant, and 0.68 (SD=0.16) without transplant. Caregivers with disease and transplant had lower EQ-5D Index scores (M=0.14, SD=0.35) than those without transplant (M=0.41, SD=0.32). The pattern was similar for EQ-5D VAS results for patient and caregiver groups. CONCLUSIONS: TTR amyloidosis is associated with substantial disruption in employment rates, work productivity, high levels of resource use, and poor HRQoL for patients and caregivers.