Several classes of medication improve survival in patients with ST-segment elevation myocardial infarction (STEMI). We sought to assess the frequency and effect of an optimal therapy upon discharge according to current international guidelines on 1-year all-cause mortality in a prospective cohort of reperfused patients with STEMI. Using data from the French Reseau Cardiologie Urgence (RESCUe) Network, we studied all patients with STEMI admitted and discharged alive from hospital between 2009 and 2013. Class I and II level guidelines were used to define the optimal therapy (OT) group. The undertreatment (UT) group comprised patients in whom at least 1 drug with a class I recommendation was missing. Multivariable Cox regression analysis with propensity score for the prescription of OT was used. Of the 5,161 patients discharged alive, 2,991 (58%) had OT. The 1-year overall survival rate was 0.99 in the OT group (95% confidence interval [CI] 0.99 to 1.00) versus 0.90 (95% CI 0.88 to 0.92) in the UT group. Patient characteristics in the UT group were worse than those in the OT group. After multivariable adjustment, the association between the OT group and mortality remained significant, with a hazard ratio of 0.12 (95% CI 0.07 to 0.22; p<0.001). Optimal secondary prevention therapy in patients with STEMI discharged alive from hospital remains independently associated with lower 1-year mortality.