© 2020 American Medical Association. All rights reserved. Importance: National guidelines recommend early palliative care for patients with advanced heart failure, which disproportionately affects rural and minority populations. Objective: To determine the effect of an early palliative care telehealth intervention over 16 weeks on the quality of life, mood, global health, pain, and resource use of patients with advanced heart failure. Design, Setting, and Participants: A single-blind, intervention vs usual care randomized clinical trial was conducted from October 1, 2015, to May 31, 2019, among 415 patients 50 years or older with New York Heart Association class III or IV heart failure or American College of Cardiology stage C or D heart failure at a large Southeastern US academic tertiary medical center and a Veterans Affairs medical center serving high proportions of rural dwellers and African American individuals. Interventions: The ENABLE CHF-PC (Educate, Nurture, Advise, Before Life Ends Comprehensive Heartcare for Patients and Caregivers) intervention comprises an in-person palliative care consultation and 6 weekly nurse-coach telephonic sessions (20-40 minutes) and monthly follow-up for 48 weeks. Main Outcomes and Measures: Primary outcomes were quality of life (as measured by the Kansas City Cardiomyopathy Questionnaire [KCCQ]: score range, 0-100; higher scores indicate better perceived health status and clinical summary scores ≥50 are considered "fairly good" quality of life; and the Functional Assessment of Chronic Illness Therapy-Palliative-14 [FACIT-Pal-14]: score range, 0-56; higher scores indicate better quality of life) and mood (as measured by the Hospital Anxiety and Depression Scale [HADS]) over 16 weeks. Secondary outcomes were global health (Patient Reported Outcome Measurement System Global Health), pain (Patient Reported Outcome Measurement System Pain Intensity and Interference), and resource use (hospital days and emergency department visits). Results: Of 415 participants (221 men; baseline mean [SD] age, 63.8 [8.5] years) randomized to ENABLE CHF-PC (n = 208) or usual care (n = 207), 226 (54.5%) were African American, 108 (26.0%) lived in a rural area, and 190 (45.8%) had a high-school education or less, and a mean (SD) baseline KCCQ score of 52.6 (21.0). At week 16, the mean (SE) KCCQ score improved 3.9 (1.3) points in the intervention group vs 2.3 (1.2) in the usual care group (difference, 1.6; SE, 1.7; d = 0.07 [95% CI, -0.09 to 0.24]) and the mean (SE) FACIT-Pal-14 score improved 1.4 (0.6) points in the intervention group vs 0.2 (0.5) points in the usual care group (difference, 1.2; SE, 0.8; d = 0.12 [95% CI, -0.03 to 0.28]). There were no relevant between-group differences in mood (HADS-anxiety, d = -0.02 [95% CI, -0.20 to 0.16]; HADS-depression, d = -0.09 [95% CI, -0.24 to 0.06]). Conclusions and Relevance: This randomized clinical trial with a majority African American sample and baseline good quality of life did not demonstrate improved quality of life or mood with a 16-week early palliative care telehealth intervention. However, pain intensity and interference (secondary outcomes) demonstrated a clinically important improvement. Trial Registration: ClinicalTrials.gov Identifier: NCT02505425.