Background - In recent decades, improvements in the management of acute coronary syndromes (ACS) have been accompanied by a marked decrease in in-hospital mortality. The trend in out-of-hospital mortality from ACS in France is less well understood. The objective was to estimate trends in in-hospital and out-of-hospital mortality from ACS in the three French registries of ischemic heart disease between 2004 and 2018, to examine their respective contributions to overall mortality from ACS, and to break down these results by geographic region. Materials and Methods - All fatal acute coronary events occurring between January 2004 and December 2018 were recorded in patients aged 35 to 74 years in the three French Monica (Monitoring trends and determinants in cardiovascular disease) registries. Trends in age-standardized mortality rates were expressed as annual percentage change (PVA). Results - Between 2004 and 2018, 17,487 fatal events were recorded, 70% of which occurred outside the hospital. Nearly 90% of out-of-hospital deaths occurred at home. Decreases in mortality rates due to ACS were greater in-hospital than out-of-hospital in Lille (APR -3.9% vs. -2.6%) and Strasbourg (APR -3.9% vs. -2.4%), but the opposite was observed in Toulouse (APR -3.5% in-hospital vs. -5.5% out-of-hospital). In Toulouse, this resulted in a decrease in the contribution of out-of-hospital mortality to overall ACS mortality from 74.9% to 67.7%. Conclusion - Between 2004 and 2018, in-hospital mortality from ACS decreased more rapidly than out-of-hospital mortality in Lille and Strasbourg. The opposite was observed in Toulouse, where the contribution of out-of-hospital mortality to overall ACS mortality was initially at a higher level. In all three centers, out-of-hospital mortality remains the predominant cause, underscoring the need to further develop strategies to reduce it, particularly by promoting first aid skills among the general population.