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The specific syndromal aspects of depression and anxiety have not been explored in relation to changes in health related quality of life (HRQOL) after cardiac surgery. The purpose of this study was to examine the impact of general stress, depression and anxiety on HRQOL after coronary artery bypass graft (CABG) surgery. Utilizing a tripartite conceptual model of depression and anxiety, it was hypothesized that general stress symptoms, rather than unique depressive or anxiogenic symptoms, would be associated with lower HRQOL 6 months after CABG surgery. Elective CABG patients (n = 226) completed baseline and postoperative self-report measures of negative emotions and HRQOL, and 193 patients completed these measures at 6-month follow-up. Multiple linear regression analyses and logit link analyses were performed to test the hypothesis. Elevated depression symptoms before and after surgery showed an association with lower and worse HRQOL for vitality and social role functioning and physical and general health. This study adds to previous research by outlining discrete associations between specific HRQOL domains, and is perhaps the first to test a theoretical model of depression and anxiety in relation to cardiac CABG patients' perceptions of HRQOL. These findings encourage further research on negative emotions and HRQOL in cardiac surgery patients and the practical implications of these findings are discussed.