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<h4>Background</h4>The important role of self-efficacy in facilitating health behavior and, in turn, promoting health outcomes has been widely presumed in the theoretical literature. However, little research has focused on the mechanism by which self-care mediates the relationship between symptom-management self-efficacy and quality of life (QOL) in breast cancer patients.<h4>Objective</h4>The purpose of this study was to examine the relationship between symptom-management self-efficacy and quality of life in Taiwanese oncology outpatients with breast cancer and then proposes self-care as a mediator between these two factors.<h4>Methods</h4>This cross-sectional study enrolled 201 oncology outpatients at one teaching hospital in metropolitan Taipei City, Taiwan. The research instruments included the Symptom-Management Self-Efficacy Scale-Cancer (SMSES-Breast Ca.), the Self-Care Scale, and the European Organization for Research & Treatment of Cancer Quality of Life Group Questionnaire (EORTC-QLQ-C30).<h4>Results</h4>Symptom-management self-efficacy (SMSE) was directly associated with the QOL of the participants (β = 5.94, p < .001). Moreover, SMSE was indirectly associated with QOL through self-care. Self-care was found to mediate the relationship between symptom-management self-efficacy and global QOL (indirect effect = 0.54, 95% CI 0.12 to 1.18). The level of 95% CI was significant.<h4>Conclusions</h4>The present study supports that self-efficacy beliefs and self-care both significantly and positively influence the quality of life of patients.