ST Segment Elevation Acute myocardial infarction (STEMI) preferred treatment is culprit artery reperfusion with primary percutaneous coronary intervention (PPCI). We ought to analyze the benefit of early reperfusion vs. optimal medical therapy in STEMI before and after the set-up of a regional STEMI network that prioritizes PPCI. Between January 2002 and December 2013, 1268 STEMI patients were consecutively admitted in a University Hospital. Patients were classified in two groups: pre-STEMI Network (January 2002-June 2009; n = 670) and post-STEMI network (July 2009-December 2013; n = 598). Vital status was available at 2-year follow-up. The STEMI network increased reperfusion (89.2% vs 64.4%, p < 0.001) mainly using PCI (99.0% vs 43.9%, p < 0.001). In univariate analysis, in-hospital mortality was significantly lower in the post-STEMI network period (2.51% vs. 7.16%, p < 0.001). After multivariate adjustment, including age, sex, comorbidities, severity and reperfusion therapy, a trend to a lower in-hospital mortality was observed (post-Network OR: 0.50, 95% CI:0.16-1.59, p = 0.24); this trend disappeared when optimal medical therapy was included in the model (post-Network OR: 1.14, 95% CI:0.32-4.08, p = 0.840). No differences in 2-year mortality were observed (post-Network HR: 0.83; CI 95%: 0.55-1.25, p = 0.37). A STEMI network with PPCI 24/7 improved reperfusion therapy, resulting in an increase on PPCI. Despite in-hospital mortality decreased with a STEMI network, 2-year mortality remained similar in both periods, pre- and post-Network. Optimal medical therapy could be as important as reperfusion therapy in a STEMI reperfusion network.