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Optimism and social support serve as protective factors against distress in medically ill patients. Very few studies have specifically explored the ways in which these variables interact to impact quality of life (QOL), particularly among patients with advanced cancer. The present study examined the role of optimism as a moderator of the relationship between social support and anxiety, depression, hopelessness, and QOL among patients with advanced cancer.Participants (N= 168) completed self-report assessments of psychosocial, spiritual, and physical well-being, including social support, optimism, hopelessness, depressive and anxious symptoms, and QOL. Hierarchical multiple regression analyses were conducted to determine the extent to which social support and optimism were associated with depressive and anxious symptomatology, hopelessness and QOL, and the potential role of optimism as a moderator of the relationship between social support and these variables.Higher levels of optimism were significantly associated with fewer anxious and depressive symptoms, less hopelessness, and better QOL. Higher levels of perceived social support were also significantly associated with better QOL. Additionally, optimism moderated the relationship between social support and anxiety, such that there was a strong negative association between social support and anxiety for participants with low optimism.This study highlights the importance of optimism and social support in the QOL of patients with advanced cancer. As such, interventions that attend to patients' expectations for positive experiences and the expansion of social support should be the focus of future clinical and research endeavors.