Background Chronic illness burdens some groups more than others. In studies of ethnic/racial groups with chronic illness, some investigators have found differences in health-related quality of life (HRQL), whereas others have not. Few such comparisons have been performed in persons with heart failure. The purpose of this study was to compare HRQL in non-Hispanic white, black, and Hispanic adults with heart failure. Methods Data for this longitudinal comparative study were obtained from eight sites in the Southwest, Southeast, Northwest, Northeast, and Midwest United States. Enrollment and 3- and 6-month data on 1212 patients were used in this analysis. Propensity scores were used to adjust for sociodemographic and clinical differences among the ethnic/racial groups. Health-related quality of life was measured using the Minnesota Living with Heart Failure Questionnaire. Results Significant ethnic/racial effects were demonstrated, with more favorable Minnesota Living with Heart Failure Questionnaire total scores post-baseline for Hispanic patients compared with both black and white patients, even after adjusting for baseline scores, age, gender, education, severity of illness, and care setting (acute vs. chronic), and estimating the treatment effect (intervention vs. usual care). The models based on the physical and emotional subscale scores were similar, with post hoc comparisons indicating more positive outcomes for Hispanic patients than non-Hispanic white patients. Conclusion Cultural differences in the interpretation of and response to chronic illness may explain why HRQL improves more over time in Hispanic patients with heart failure compared with white and black patients.