To evaluate in a real-world primary percutaneous coronary intervention (pPCI) registry the impact of the evolution of evidence-based treatments on prognosis.STEMI patients undergoing pPCI at the University Hospital of Trieste, Italy, were enrolled. The first cohort (old treatments cohort) included STEMI patients treated between January-2007 and December-2012, and the second cohort (new treatments cohort), between January-2013 and December-2020. Inverse Probability of Treatment Weighting (IPTW) Cox regression models as well as multivariable Cox regression models were performed to assess the risk of a composite primary endpoint (PE) of all cause death, reinfarction and re-PCI at 5 years.A total of 2425 STEMI patients were enrolled. At multivariable Cox regression, the new-treatments cohort had lower risk of PE and mortality. Weighted (IPTW) Cox proportional hazard models confirmed the lower risk of the new treatments cohort for PE (HR 0.72; 95% CI 0.56-0.91, p = 0.007) and 5-year mortality (HR 0.70, 95%CI 0.54-0.91, p = 0.009). When considering both clinical and procedural variables, complete revascularization (HR 0.46, 95%CI 0.27-0.80, p = 0.006) and the administration of prasugrel or ticagrelor (HR 0.72, 95%CI 0.52-0.99, p = 0.013) were independent predictors of PE as well as of 5-year mortality. Patients receiving prasugrel or ticagrelor or drug eluting stent were at lower risk of 1-year stent thrombosis (HR 0.50, 95%CI 0.28-0.90, p = 0.021).In a real-word STEMI population the prognosis of patients has improved in the last decades, and this was associated to the use of new antithrombotic treatments and to the implementation of complete revascularization.