Abstract INTRODUCTION: Depression seems to be an independent risk factor for cardiovascular disease (CVD). Little is known about the effects of treatment of depression on CAD risk factors. The objective of this study was to determine whether cardiac risk is altered following 8 weeks of treatment of depression with fluoxetine. A secondary aim was to examine whether an omega-3 fatty acid eicosapentaenoic acid (EPA) plus fluoxetine affected the change in CAD risk compared with fluoxetine alone. METHODS: Forty patients with a diagnosis of major depression were randomly allocated to receive daily 20 mg fluoxetine plus either 1 g EPA or its placebo for 8 weeks. The 24-item Hamilton Rating Scale for Depression (a validated scoring system usually used in studies of antidepressant medication) was utilized to evaluate clinical symptoms of patients. Cardiac risk was estimated using fasting plasma or serum levels of total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol LDL-C, cortisol and C-reactive protein (CRP) at baseline and at week 8. RESULTS: Depression severity was decreased significantly in both groups. CRP and cortisol decreased significantly after treatment. EPA plus fluoxetine did not affect the change in CRP and cortisol compared to fluoxetine alone. Total cholesterol did not change significantly after 8 weeks of treatment. LDL-C/HDL-C ratio increased after treatment without difference between treatment groups. CONCLUSIONS: Treatment of patients with major depression by fluoxetine with or without EPA could lower CAD risk due to decreases in cortisol and CRP. Although LDL to HDL ratio increased, its importance in CAD risk is not clear, as LDL size and HDL subclasses were not measured in this study. EPA plus fluoxetine did not have any significant effect on the change of these risk factors compared to fluoxetine alone in this 8-week trial. Keywords: cardiovascular disease risk, depression, fluoxetine, omega-3.