Background: Heart failure (HF) patients who follow the treatment regimen and attend to symptoms before they escalate are assumed to have better health-related quality of life (HRQOL) than those with poor self-care, but there are few data available to support or refute this assumption. Objective: The objective of the study was to describe the relationship between HF self-care and HRQOL in older (≥65 years old) adults with moderate to advanced HF. Methods: Self-care was measured using the 3 scales (maintenance, management, and confidence) of the Self-care of Heart Failure Index. Scores range from 0 to 100, with higher numbers indicating better self-care. Health-related quality of life was measured with the Minnesota Living With Heart Failure Questionnaire, a 2-subscale (physical and emotional) instrument. Lower numbers on the Minnesota Living With Heart Failure Questionnaire indicate better HRQOL. Pearson correlations, independent-samples t-tests, and linear and logistic regression modeling were used in the analysis. Results: In 207 adults (72.9 [SD, 6.3] years), New York Heart Association class III (82%) or IV, significant linear associations were observed between self-care confidence and total (r = −0.211; P = .002), physical (r = −0.189; P = .006), and emotional HRQOL (r = −0.201; P = .004). Patients reporting better (below median) HRQOL had higher confidence scores compared with patients reporting above-median HRQOL scores (58.8 [19.2] vs 52.8 [19.6]; P = .028). Confidence was an independent determinant of total (βs = −3.191; P = .002), physical (βs = −2.346; P = .002), and emotional (βs = −3.182; P = .002) HRQOL controlling for other Self-care of Heart Failure Index scores, age, gender, and New York Heart Association class. Each 1-point increase in confidence was associated with a decrease in the likelihood that patients had worse (above median) HRQOL scores (odds ratio, 0.980 [95% confidence interval, 0.963–0.998]) with the same controls. No significant associations were found between self-care maintenance or management and HRQOL. Conclusions: The degree of individual confidence in HF self-care is related to HRQOL, but self-reports of specific maintenance and management behaviors are not. Interventions that improve self-care confidence may be particularly important in older adults with moderate to advanced HF.