ABSTRACT Spirituality and gratitude are associated with wellbeing. Few if any studies have examined the role of gratitude in heart failure (HF) patients or whether it is a mechanism through which spirituality may exert its beneficial effects on physical and mental health in this clinical population. This study examined associations bet ween gratitude, spiritual wellbeing, sleep, mood, fatigue, cardiac-specific self-efficacy, and inflammation in 186 men and women with Stage B asymptomatic HF (age 66.5 years ±10). In correlational analysis, gratitude was associated with better sleep (r=-.25, p<0.01), less depressed mood (r=-.41, p<0.01), less fatigue (r=-.46, p<0.01), and better self-efficacy to maintain cardiac function (r=.42, p<0.01). Patients expressing more gratitude also had lower levels of inflammatory biomarkers (r=-.17, p<0.05). We further explored relationships among these variables by examining a putative pathway to determine whether spirituality exerts its beneficial effects through gratitude. We found that gratitude fully mediated the relationship between spiritual wellbeing and sleep quality (z=−2.35, SE=.03, p=.02) and also the relationship between spiritual wellbeing and depressed mood (z=−4.00, SE=.075, p<.001). Gratitude also partially mediated the relationships between spiritual wellbeing and fatigue (z=−3.85, SE=.18, p<.001), and between spiritual wellbeing and self-efficacy (z=2.91, SE=.04, p=.003). In sum, we report that gratitude and spiritual wellbeing are related to better mood and sleep, less fatigue, and more self-efficacy, and that gratitude fully or partially mediates the beneficial effects of spiritual wellbeing on these endpoints. Efforts to increase gratitude may be a treatment for improving wellbeing in HF patients’ lives and be of potential clinical value.