Journal of Medical Internet Research - International Scientific Journal for Medical Research, Information and Communication on the Internet #Preprint #PeerReviewMe: Warning: This is a unreviewed preprint. Readers are warned that the document has not been peer-reviewed by expert/patient reviewers or an academic editor, may contain misleading claims, and is likely to undergo changes before final publication, if accepted, or may have been rejected/withdrawn. Readers with interest and expertise are encouraged to sign up as peer-reviewer, if the paper is within an open peer-review period. Please cite this preprint only for review purposes or for grant applications and CVs (if you are the author). Background: Despite the relatively high prevalence of low health literacy among individuals living with Chronic Obstructive Pulmonary Disease (COPD), limited empirical attention has been paid to the cognitive and health-literacy-related skills that can uniquely influence patients’ health-related quality of life (HRQoL) outcomes. Objective: To examine how health literacy, eHealth literacy, and COPD knowledge are associated with both generic and lung-specific HRQoL in people living with COPD. Methods: Adults from the COPD Foundation’s National Research Registry (N = 174) completed a cross-sectional web-based survey that assessed socio-demographic characteristics, comorbidity status, COPD knowledge, health literacy, eHealth literacy, and generic HRQoL. Hierarchical linear regression models were tested to examine the roles of health literacy and eHealth literacy on generic (Model 1) and lung-specific (Model 2) HRQoL, after accounting for socioeconomic and comorbidity covariates. Spearman rank correlations examined associations between ordinal HRQoL items and statistically significant hierarchical predictor variables. Results: Health literacy, eHealth literacy and COPD knowledge accounted for 9% of variance in generic HRQoL (Adj. R2=21%), F(9, 164) = 6.09, P<.001. After adjusting for potentially confounding factors, health literacy (b = .08, SE = .02, 95% CI = [0.04, 0.12]) was the only predictor positively associated with generic HRQoL (P < .001). Higher health literacy scores were significantly (P < .05) associated with better scores on all five generic HRQoL dimensions. Adding health literacy, eHealth literacy and COPD knowledge as predictors explained an additional 7.40% of variance in lung-specific HRQoL (Adj. R2=26.40%), F(8, 161) = 8.59, P < .001). After adjusting for covariates, both health literacy (b = 2.63, SE = .84, 95% CI = [.96, 4.29], P < .001) and eHealth literacy (b = 1.41, SE = .67, 95% CI = [.09, 2.73], P < .001) were positively associated with lung-specific HRQoL. Health literacy was associated with better scores quantifying the impact of most lung-specific HRQoL indicators (i.e., cough frequency, chest tightness, activity limitation at home, confidence leaving home, sleep quality, and energy level). eHealth literacy was positively associated with 5 of 8 (60%) lung-specific HRQoL indicators. After adjusting for confounding variables, COPD knowledge (b = -.56, SE = .29, 95% CI = [-1.22, -.004], P < .05) was inversely associated with lung-specific HRQoL. Conclusions: Health literacy, but not eHealth literacy, was positively associated with generic HRQoL. However, both health literacy and eHealth literacy were positively associated with lung-specific HRQoL, with higher COPD knowledge indicative of lower lung-specific HRQoL. Results confirm the importance of considering both health and eHealth literacy levels when designing patient education and self-management support programs for people living with COPD. Future research should explore the impact of delivering interventions aimed at improving eHealth and health literacy among COPD patients, particularly when overarching intervention goals are to enhance HRQoL.