Optimization of medical therapy during discharge planning is vital for improving patient outcomes after hospitalization for acute myocardial infarction (AMI). However, limited information is available about recent trends in the prescribing of evidence-based medical therapies in these patients, especially from a population-based perspective. We describe decade-long trends in the discharge prescribing of aspirin, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, β blockers, and statins in hospital survivors of AMI. The study population consisted of 5,253 patients who were discharged from all 11 hospitals in central Massachusetts after AMI in 6 biennial periods from 2001 to 2011. Combination medical therapy (CMT) was defined as the prescription of all 4 cardiac medications at hospital discharge. The average age of this patient population was 69.2 years and 57.7% were men. Significant increases were observed in the use of CMT, from 25.6% in 2001 to 48.7% in 2011, with increases noted for each of the individual cardiac medications examined. Subgroup analysis also showed improvement in discharge prescriptions for P2Y12 inhibitors in patients who underwent a percutaneous coronary intervention. Presence of a do-not-resuscitate order, before co-morbidities, hospitalization for non-ST-segment elevation myocardial infarction, admission to a nonteaching hospital, and failure to undergo cardiac catheterization or a percutaneous coronary intervention were associated with underuse of CMT. In conclusion, our study demonstrates encouraging trends in the prescribing of evidence-based medications at hospital discharge for AMI. However, certain patient subgroups continue to be at risk for underuse of CMT, suggesting the need for strategies to enhance compliance with current practice guidelines.