Background: Low health literacy (HL) is a known barrier to care and is associated with worse overall health status. The association of HL with disease-specific health status in heart failure (HF) patients is unknown. To address this gap we used data from Hopeful Heart , a randomized trial examining the impact of two 12-month treatment strategies in patients with HF and depression vs usual care. Methods: Health literacy was assessed at baseline via a brief screening tool previously validated in patients with HFrEF, classifying patients into adequate vs. low literacy. HF-specific health status was quantified with the 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12) at baseline, 3, 6, and 12 months. Using linear regression, we estimated the association of low HL with 12-month KCCQ-12 Summary Score, adjusting for treatment group, age, gender and LVEF. We also assessed the association of low HL with 12-month change in KCCQ-12, additionally adjusting for baseline score. Finally, we analyzed depression severity as a moderator in the interaction between HL and PROMIS-D depression score. Results: Among 756 patients, those with low HL (N=235, 31%) were similar in demographics (65±13 vs 64±13 years; 43% vs. 44% female; 24% vs. 28% non-White), but had less education (36% vs. 61% high school) and employment (10% vs. 19%) compared to those with adequate HL. Mean KCCQ-12 scores were consistently lower in participants with low HL at all time points (Figure). After adjusting for treatment group, age, sex, and LVEF, low HL was strongly associated with lower 12-month KCCQ-12 score (-9.5 points, CI [-13.7,-5.3]). After adjustment for baseline score, low HL remained associated with less improvement in KCCQ-12 (-5.9 points, CI [-9.7, -2.2]). Depressive symptoms did not moderate this association (interaction p=0.72). Conclusion: In patients with HF, low HL is associated with worse disease-specific health status and with poorer recovery in health status at 12-month follow up.