Patients who survive an acute myocardial infarction (MI) are at increased risk of subsequent major cardiovascular events and cardiac (often sudden) death. The use of highly concentrated and purified omega-3 polyunsaturated fatty acids (n-3 PUFAs), in addition to standard secondary prevention after MI, results in a significant reduction in the risk of sudden death. This study assessed the cost-effectiveness of adding n-3 PUFAs to the current secondary prevention treatment after acute MI in 5 countries: Australia, Belgium, Canada, Germany, Poland. Based on the clinical outcomes of GISSI-Prevenzione (MI, stroke, revascularisation rate and mortality), a decision-model was built in DataPROTM. The implications of adding n-3 PUFAs to standard treatment in patients with a recent history of MI were analysed from the health care payer's perspective. The time horizon was 3.5 years (identical to GISSI-Prevenzione). Event costs were based on literature data. Life expectancy data for survivors of cardiac disease were taken from the Saskatchewan database and then country-adjusted. Results are expressed as extra cost (Euro) per life-year gained (LYG). Annual discounting of 5% was applied to health effects and costs. Treatment with highly concentrated n-3 PUFAs yielded between 0.260 (Poland) and 0.284 (Australia) LYG, at an additional cost of Euro 807 (Canada) to Euro 1,451 (Belgium). The incremental cost-effectiveness ratio (ICER) varied between Euro 2,867 (Canada) and Euro 5,154 (Belgium) per LYG. Sensitivity analyses on effectiveness, cost of complications and discounting proved the robustness of the results. A 2nd order Monte Carlo simulation based on the 95% CIs obtained from GISSI showed that highly concentrated n-3 PUFAs are cost-effective in more than 99% of patients (assuming societal willingness to pay threshold of Euro 20,000/LYG). Including health care costs incurred during the remaining life-years considerably increased total costs, but had no impact on the ICER-based treatment recommendation. Adding highly concentrated n-3 PUFAs to standard treatment in the secondary prevention after MI appears to be cost-effective in the 5 countries studied.