BACKGROUND: Women with acute myocardial infarction (AMI) experience higher mortality rates than men. This disparity is influenced by factors such as older age, greater comorbidity burden, atypical symptom presentation and delays in treatment. This study analysed patients with AMI (2003-2018) from the Lombardy Health Database (Italy) to examine sex differences in in-hospital and 1-year mortality and the role of age, percutaneous coronary intervention (PCI) and postdischarge therapy. METHODS AND RESULTS: Among 263 564 patients with AMI (93 363 women, 170 201 men), primary and secondary endpoints were in-hospital and 1-year mortality, respectively. Path analysis evaluated the direct and indirect effects of sex on outcomes, incorporating age, PCI and postdischarge therapy as mediators. Women had higher in-hospital (10% vs 5%; p<0.0001) and 1-year mortality (24% vs 14%; p<0.0001) but were less likely to receive PCI (40% vs 61%; p<0.0001) and postdischarge therapy (dual antiplatelet therapy 53% vs 63%; ACE inhibitors/angiotensin receptor blockers 60% vs 64%; beta blockers 53% vs 61%; lipid-lowering drugs 45% vs 58%; p<0.0001 for all differences). After adjusting for age, major comorbidities, PCI and postdischarge treatment, mortality differences were no longer significant (adjusted OR 1.04; 95% CI 0.99 to 1.07 for in-hospital mortality) or even reversed (adjusted HR 0.94; 95% CI 0.92 to 0.96 for 1-year mortality). Path analysis showed that female sex directly contributed 12% to in-hospital mortality and 4% to 1-year mortality, while age and undertreatment accounted for most of the disparity (88% and 96%, respectively). CONCLUSION: Women with AMI face higher mortality largely due to older age and undertreatment during hospitalisation and after discharge. Addressing these gaps could improve outcomes.