Introduction <p>The Burden of Disease survey characterized the humanistic burden of transthyretin amyloid cardiomyopathy (ATTR-CM) in 208 international patients not receiving disease-modifying therapy and their primary caregivers.</p> Methods <p>Post hoc univariate analyses evaluated the relationships between patients’ current symptoms and ability to complete activities of daily living (ADLs) with their caregivers’ Zarit Burden Interview (ZBI), Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue, and Hospital Anxiety and Depression Survey Anxiety (HADS-A) and Depression (HADS-D) subscale scores.</p> Results <p>Most patients had wild-type ATTR-CM (91%; <i>n</i> = 141/155) and a New York Heart Association functional classification of&#xa0;I/II (78%; <i>n</i> = 156/199). Caregivers (<i>n</i> = 208) were a median age of 68&#xa0;years, 85% were female, and 66% lived with the patient. Current patient symptoms of paralysis, heart failure, weakness (especially in the legs), leg pain, leg and ankle swelling, loss of sensation in the legs/arms, fatigue, insomnia, and weight loss were associated with a significantly (<i>P</i> &lt; 0.05) higher caregiver ZBI score. Many of these symptoms were also associated with significantly (<i>P</i> &lt; 0.05) higher PROMIS Fatigue and HADS-A scores; heart failure and weakness (especially in the legs) were associated with a significantly (<i>P</i> &lt; 0.05) higher HADS-D score. Inability of patients to independently clean, bathe, cook, get in/out of bed, or walk were associated with significantly (<i>P</i> &lt; 0.05) higher caregiver ZBI and HADS-D scores. Inability to independently clean and walk were associated with significantly (<i>P</i> &lt; 0.05) higher PROMIS Fatigue and HADS-A scores.</p> Conclusions <p>Burden is higher in caregivers of patients with ATTR-CM who have specific symptoms (including those causing disability) or an inability to independently complete ADLs.</p> <p>Graphical Abstract available for this article.</p> Graphical Abstract <p></p>