Background: Increased spiritual well-being is related to quality of life (QOL) in patients with heart failure (HF). However, consistent and deliberate integration of spirituality into HF patient care has received limited attention. Objective: The aim of this study was to evaluate the feasibility, acceptability, and preliminary evidence regarding the efficacy of a resource-sparing psychospiritual intervention to improve QOL in HF patients. Methods: A 12-week mail-based intervention addressing spirituality, stress, coping, and adjusting to illness was developed and tested using a mixed-methods, 1-group pretest-posttest pilot study design. A convenience sample of patients with HF completed prestudy and poststudy questionnaires, including the Kansas City Cardiomyopathy Questionnaire, Patient Health Questionnaire, Meaning in Life Questionnaire, and Functional Assessment of Chronic Illness Therapy-Spiritual. Research staff conducted semistructured interviews with program completers. Interviews were coded and analyzed using conventional content analysis. Results: Participants (N = 33; 82% male; mean age, 61 years) completed 87% of baseline data collection, an average of 9 intervention modules, and 55% of poststudy questionnaires. Participants rated all the modules as at least moderately helpful, and qualitative themes suggested that patients found the intervention acceptable and beneficial. Most participants believed spirituality should continue to be included, although they disagreed on the extent to which religion should remain. Participants who completed the intervention reported evidence suggesting increased QOL (Kansas City Cardiomyopathy Questionnaire; effect size [ES], 0.53), decreased depressive symptoms (Patient Health Questionnaire-9; ES, 0.62), and less searching for meaning (Meaning in Life Questionnaire; ES, 0.52). Conclusions: Results indicate that a module-based program integrating spirituality and psychosocial coping strategies was feasible and acceptable and may improve QOL. This preliminary study suggests that clinicians be open to issues of spirituality as they may relate to QOL in patients with HF. Future research will test a revised intervention.