Regular fish consumption is associated with lower risk of cardiovascular disease and premature mortality. However, recent randomised control trials (RCT) of fish oil supplements have produced variable results, interpreted to not support either beneficial or adverse effects of long chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the treatment or prevention of cardiovascular disease (Nestel P, Heart Lung Circ 2015;24:769-779). This review considers issues key to understanding the contradiction. 1) When is a placebo not a control? Most RCT report no exclusion criteria for fish eaters and even fewer analyse n-3 PUFA status. Even after exclusions, trials report overlap of tissue n-3 PUFA status in control and treated groups. 2) Cardiac effects (prevention of: sudden death; heart failure) involve myocardial membrane incorporation of DHA. The LC n-3 PUFA intake in cohort studies derives from seafood, providing DHA>EPA, whereas most RCT give supplements rich in EPA, low in DHA. 3) Nutritional and therapeutic dose effects of LC n-3 PUFA are defined by different mechanisms. Direct cardiac effects on heart rate, heart failure and sudden death occur at lower doses than influence classical coronary artery disease risk factors and inflammation. 4) RCT designs combine cardiac and arterial disease populations and composite endpoints, which erroneously propose a common substrate and presume a common mechanism of action. Conclusion: Understanding the pleiotropic mechanisms of action and dose differences of LC n-3 PUFA effects, and better interpretation of the epidemiology and experimental evidence must be used to improve RCT design and analysis in order to resolve the apparent contradictory effects of LC n-3 PUFA supplements and eating fish.