The relationship between myocardial infarction (MI), depression and cardiac death is not well understood. There is evidence that poly unsaturated fatty acid (PUFA) metabolism and composition in phospholipids and cholesterylesters are involved in the pathophysiology of affective disorders and cardiac dysregulation. In this paper the relationship of PUFAs with 1) cardiac events 2) depressive disorder and 3) the inflammatory response system (IRS) will be reviewed. The underlying pathophysiologic mechanisms relate to the effects of dietary fatty acids on the IRS, the HPA-axis, serotonin metabolism and platelet reactivity. These effects are the result of the important effects of PUFAs on the structure and function of localized membrane domains, their involvement in eicosanoid synthesis and their influence on intra-cellular signalling pathways and gene expression. Antidepressive treatment has been shown to have immunosuppressive effects in healthy volunteers. In patients with bipolar disorder or schizophrenia, PUFA supplementation resulted in significant symptom reduction. In the ongoing substudy of the MIND-IT, the effects of antidepressive treatment on immune status, PUFA composition in serum phospholipids and cholesterylesters and whole blood serotonin in depressive post-MI patients will be investigated. More knowledge on the relationships between PUFAs in diet, IRS parameters and serotonin metabolism may alter treatment strategies in the prevention of both cardiac death and the occurrence of depressive disorder in cardiac patients.