PURPOSE: Depression is common in people with coronary heart disease (CHD) and predicts worse cardiac outcomes. Cognitive and behavioral mechanisms have been proposed to explain this association, although the mediating role of these mechanisms remains unclear. We conducted a prospective cohort study to investigate whether the impact of depression on subsequent impaired health-related quality of life (HRQoL) was mediated by cognitive and behavioral pathways. METHODS: Demographic and medical characteristics, depression (Hospital Anxiety and Depression Scale), illness cognitions (Brief Illness Perceptions Questionnaire and Cardiac Anxiety Questionnaire), awareness of somatic symptoms (Symptom Checklist-90, revised version), and health behaviors were recorded from 255 primary care patients with CHD. The Short Form-36 was completed by 201 participants 6 months later. RESULTS: Twenty-five participants (9.8%) were depressed at baseline. Short Form-36 Physical Component Score (PCS) was significantly lower in participants who were depressed (mean PCS score = 29.8 versus 38.0, P =.001). After controlling for demographic and medical variables, depression continued to be associated with subsequent PCS [B =-0.84(0.20), P <.0005]. When cardiac anxiety, awareness of somatic symptoms, and negative illness perceptions were added to the regression model, depression no longer continued to make a significant independent contribution to the model [B =-0.3(0.2), P =.16]. Maladaptive health behaviors did not fulfill criteria to mediate the relationship between depression and impaired healthrelated quality of life. CONCLUSIONS: Findings indicate that the impact of depression on HRQoL could be mediated by cardiac anxiety, awareness of somatic symptoms, and negative illness perceptions, but not maladaptive health behaviors. Psychological interventions targeting these mediators have potential to improve HRQoL in people with CHD. Copyright © 2011 Wolters Kluwer Health | Lippincott Williams &Wilkins.