The purpose of this study was to examine the association of psychosocial factors (depression, social support, and health-related quality of life) with heart rate variability (HRV) in patients with heart failure. The sample comprised 91 outpatients from a medical center. Data were collected using the Beck Depression Inventory–II, Medical Outcomes Study (MOS) Social Support Survey, and Minnesota Living With Heart Failure Questionnaire. HRV was measured in terms of time-domain parameters from a 24-hr ambulatory Holter electrocardiogram. After adjusting for demographic and clinical variables, quality of life and social support were significantly associated with HRV. HRV (time-domain measures) was significantly higher in patients who perceived better quality of life and more social support. Our findings suggest that nurses could screen early for patients’ risk of adverse psychosocial conditions and suggest online or other social supportive interventions to help at-risk patients minimize the negative associations with HRV.