Spiritual well-being (Sp-WB) is a resource that supports adaptation and resilience, strengthening quality of life (QOL) in patients with cancer or other chronic illnesses. However, the relationship between Sp-WB and QOL in patients with chronic graft-versus-host disease (cGVHD) remains unexamined. Fifty-two participants completed the Functional Assessment of Chronic Illness Therapy-Spiritual WellBeing (FACIT-Sp) questionnaire as part of a multidisciplinary study of cGVHD. Sp-WB was generally high. Those with the lowest Sp-WB had a significantly longer time since diagnosis of cGVHD (P = 0.05) than those with higher Sp-WB. There were no associations between Sp-WB and demographics, cGVHD severity, or intensity of immunosuppression. Participants with the lowest Sp-WB reported inferior physical (P = 0.0009), emotional (P = 0.003), social (P = 0.027), and functional well-being (P < 0.0001) as well as lower overall QOL (P < 0.0001) compared with those with higher Sp-WB. They also had inferior QOL relative to population norms. Differences between the group reporting the lowest Sp-WB and those groups who reported the highest Sp-WB scores consistently demonstrated a significant difference for all QOL subscales and for overall QOL. Controlling for physical, emotional, and social well-being, Sp-WB was a significant independent predictor of contentment with QOL. Our results suggest that Sp-WB is an important factor contributing to the QOL of patients with cGVHD. Research is needed to identify factors that diminish Sp-WB and to test interventions designed to strengthen this coping resource in patients experiencing the late effects of treatment.