Marine n-3 PUFA have potential antiatherogenic, antithrombotic, and antiinflammatory properties. However, recent research have addressed the antiarrhythmic effect of these fatty acids as a major explanation for their beneficial role in IHD and such an effect may explain the reduction in the incidence of SCD observed among fish eaters. SCD remains a serious problem in the Western Countries and although prevention of SCD is one of the main targets in modern cardiology the incidence of SCD has not declined during the past decades. Therefore, there is a need for other approaches to reduce the incidence of SCD. Thus, the aims of this study were 1) to study the impact of n-3 PUFA on 24-hour HRV, a recognized predictor of arrhythmic events and SCD in high-risk patients and in healthy subjects, and 2) to review the current knowledge about n-3 PUFA and the risk of SCD in humans and the proposed actions of n-3 PUFA responsible for an antiarhythmic effect. Subjects eating a modest amount of marine n-3 PUFA have an approximately 50% reduction in the risk of SCD compared to subjects not eating fish and in one study there was a close negative association between the risk of SCD and the cellular level of n-3 PUFA. Two large intervention studies support a beneficial effect of n-3 PUFA on the risk of SCD. In the DART study from 1989 a significant 29% reduction was found among post-MI men advised to eat fatty fish twice a week compared to those not advised so. This reduction could not be explained by an antiatherosclerotic or an antithrombotic effect of n-3 PUFA and an antiarrhythmic effect was considered operative. Ten years later the GISSI Prevenzione trial showed a 45% reduction in SCD among post-MI patients given one fish oil capsule daily (equal to 0.85 g of n-3 PUFA). The mechanisms behind the protection against SCD from marine n-3 PUFA have mainly been addressed in animal and in-vitro studies in which n-3 PUFA have shown profound antiarrhythmic effects. Based on the emerging hard end point data on the effect of n-3 PUFA on SCD in humans it is of importance to investigate if n-3 PUFA have actions in humans comparable to data from non-human studies. A surrogate for the risk of developing ventricular arrhythmias and SCD in humans is 24-hour HRV. Thus, in patients with IHD the risk of malignant ventricular arrhythmias and SCD is increased with decreased HRV. On the opposite, pharmacological interventions resulting in an improved patient survival have been associated with an increased HRV. In our studies we found positive associations between the cellular levels of marine n-3 PUFA and HRV in post-MI patients and in patients referred for coronary angiography suspected of IHD. Also, in these patients cellular levels of marine n-3 PUFA were independently correlated with HRV. When post-MI patients were given 5.2 g of marine n-3 PUFA daily for 12 weeks their HRV significantly increased. These findings may help explain why marine n-3 PUFA offer protection against SCD in patients with IHD. Patients with CRF and patients with DM comprise patient populations with an increased risk of SCD and an attenuated HRV. In these two groups of patients we found a close positive association between the cellular level of marine n-3 PUFA and HRV suggesting a beneficial effect of marine n-3 PUFA on HRV. Further research with dietary intervention with n-3 PUFA to CRF and DM patients should clarify if this effect can be translated into a reduction of coronary events. A decreased HRV may predict a poor outcome among healthy subjects due to an increased risk of SCD. We found a close positive association between cellular levels of marine n-3 PUFA and HRV in healthy men but not in healthy women. Dietary intervention with either 2.0 g or 6.6 g of marine n-3 PUFA daily for 12 weeks revealed a dose-dependent increase in HRV among men with a low base-line HRV. The results may help explain why dietary marine n-3 PUFA may reduce the risk of SCD in healthy men. It is a novel observation that n-3 PUFA have a beneficial impact on HRV in humans. The results from non-human studies showing effects of n-3 PUFA on sodium channels, calcium-channels and adrenergic receptors may, if applicable to humans, explain this effect of n-3 PUFA on HRV. However, n-3 PUFA may also cause a central modulation of HRV and, n-3 PUFA may thus modulate HRV both at the level of the brain and in the heart. In conclusion, the data suggest that marine n-3 PUFA have a beneficial impact on HRV in patients at high risk of SCD and in healthy men. Furthermore, our data may indicate that the protective effect of n-3 PUFA on SCD found among post-MI patients and healthy subjects is caused by a modulation of autonomic control with increased vagal tone. Therefore, given the safety and low cost of implementing a modest amount of marine n-3 PUFA in the diet, an adequate dietary fish intake may have a significant role to play in the primary and secondary prevention of out-of-hospital SCD.