Patients with congestive heart failure (CHF) often report high levels of religiousness, which may mitigate the stressfulness of their condition. However, religious struggle, reflecting negative attitudes toward God and a strained meaning system, may be detrimental to well-being. Little is known about religious struggle in those with CHF, particularly in relation to physical health and well-being over time. We examined associations of religious struggle and subsequent mental and physical well-being in 101 endstage CHF patients who completed questionnaires twice over 3 months. Religious struggle predicted higher number of nights subsequently hospitalized, higher depression, and marginally lower life satisfaction. When controlling for baseline levels of well-being, effectively assessing change in those outcomes, religious struggle remained a significant predictor of hospitalization and also emerged as a marginally significant predictor of lower physical functioning. Struggle was unrelated to health-related quality of life. Post-hoc analyses suggest that these effects were particularly strong for those endorsing greater religious identification. Religious struggle appears to have a potentially negative impact on well-being in advanced CHF; therefore, helping patients to address issues of struggle may meaningfully lessen the personal and societal costs of CHF.