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Background Few data exist on regional systems of care for the treatment of ST ‐segment–elevation myocardial infarction ( STEMI ) in developing countries. Our objective was to describe temporal trends in 30‐day mortality and identify predictors of mortality among STEMI patients enrolled in a prospective registry in Brazil. Methods and Results From January 2011 to June 2013, 520 patients who received initial STEMI care at 23 nonspecialized public health units or hospitals, some of whom were transferred to a public cardiology referral center, were identified through a regional STEMI network supported by telemedicine and the local prehospital emergency medical service. We stratified patients into five 6‐month periods based on presentation date. Mean age (± SD ) of patients was 62.0 (±12.2) years, and 55.6% were men. The mean Global Registry of Acute Coronary Events ( GRACE ) score was 145 (±34). Overall mortality at 30 days was 15.0%. Use of dual antiplatelet therapy and statins increased significantly from baseline (January 2011) to period 5 (June 2013): 61.8% to 93.6% ( P P P P =0.001). Thirty‐day mortality rates decreased from 19.8% to 5.1% ( P GRACE score, history of previous stroke, lack of transfer to the referral center, and lack of use of optimized medical therapy. Conclusions Implementation of a regional STEMI system was associated with lower mortality and higher use of evidence‐based therapies.