•Caregivers of older patients with advanced heart failure awaiting long-term mechanical circulatory support (MCS) or heart transplantation (with or without MCS prior to transplant) reported similarly high levels of health-related quality of life (HRQOL) and low levels of depressive symptoms.•Anxiety was higher in caregivers of older patients awaiting long-term MCS than in both groups of caregivers of older patients awaiting heart transplantation.•Caregiver comorbidities and anxiety, which were associated with worse HRQOL of caregivers of the older, advanced-HF patients, provide targets to guide strategies to support these caregivers. We compared health-related quality of life (HRQOL), depressive symptoms, anxiety, and burden in caregivers of older patients with heart failure based on the intended therapy goal of the patient: awaiting heart transplantation (HT) with or without mechanical circulatory support (MCS) or prior to long-term MCS; and we identified factors associated with HRQOL. Caregivers (n = 281) recruited from 13 HT and MCS programs in the United States completed measures of HRQOL (EQ-5D-3L), depressive symptoms (PHQ-8), anxiety (STAI-state), and burden (Oberst Caregiving Burden Scale). Analyses included ANOVA, Kruskal-Wallis tests, χ2 tests, and linear regression. The majority of caregivers were female, white spouses with ≤ 2 comorbidities, median Q1,Q3 age = 62 57.8, 67.0 years. Caregivers (HT with MCS = 87, HT without MCS = 98, long-term MCS = 96) reported similarly high baseline HRQOL (EQ-5D-3L visual analog scale median score = 90; P = 0.67 for all groups) and low levels of depressive symptoms. STAI-state median scores were higher in the long-term MCS group vs the HT groups with and without MCS, (38 vs 32 vs 31; P < 0.001), respectively. Burden (task: time spent/difficulty) differed significantly among groups. Caregiver factors (number of comorbidities, diabetes and higher anxiety levels) were significantly associated with worse caregiver HRQOL, R2 = 26%. Recognizing caregiver-specific factors, including comorbidities and anxiety, associated with the HRQOL of caregivers of these older patients with advanced HF may guide support strategies. Display omitted