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Summary Aim of the study Animal studies have demonstrated evidence of an anti-arrhythmic effect of marine n -3 fatty acids (FAs). In humans the same mechanism may explain the observed reduction in sudden cardiac death (SCD) associated with intake of fish. Whether high levels of n -3 FAs could protect against ventricular fibrillation (VF) during the acute ischaemic phase of a myocardial infarction (MI) is, however, not known. Materials and methods We measured red blood cell content of eicosapentaenoic acid (EPA)+docosahexaenoic acid (DHA) expressed as a percentage of total FAs (the omega-3 index) at admission in 460 patients hospitalised with an acute coronary syndrome. Out of 265 patients suffering their first MI, 10 (cases) experienced an episode of VF during the initial 6h of symptom onset. The omega-3 index of these patients was compared to that of 185 first-MI patients (controls) free of VF for at least 30 days post-admission. Results The median value of the omega-3 index in the VF cases was 4.88% as compared to 6.08% in the controls ( p =0.013). After adjustment for age, sex, ejection fraction, high-sensitivity C-reactive protein, use of beta-blocker, differences of infarct characteristics and previous angina pectoris, a 1% increase of the omega-3 index was associated with a 48% reduction in risk of VF (odds ratio (OR) 0.52, 95% confidence interval (CI) 0.28–0.96; p =0.037). Conclusion Our study supports an anti-arrhythmic effect of n -3 FAs through their incorporation into myocardial cell membranes, reducing the risk of VF during ischaemia.