Background. Based on epidemiological data, clinical trials, and meta-analytic reviews, omega-3 polyunsaturated fatty acids (n-3 PUFAs) seem to be a biological link between depression and cardiovascular diseases (CVDs). Presentation. Involvement of n-3 PUFAs in depression and CVDs may be associated with a chronic, low-grade, inflammation. We hypothesize that n-3 PUFAs link depression and CVDs via "PUFA-prostaglandin E2 (PGE2) cascade." Testing. To further support our hypothesis, case-control studies are needed to test the role of COX2 and PLA2 functions in depression and in CVDs. In addition, the effects of n-3 PUFAs on cardiovascular markers in depression and on depressive symptoms in CVDs should be investigated in clinical trials. Finally, the effects of manipulating COX2 and PLA2 functions on depression-like behaviors and cardiovascular functions could be explored in animal studies. Implications. n-3 PUFAs might be a promising treatment for both cardiovascular diseases and depression via its anti-inflammatory, cardioprotective, and neuroprotective effects.