BACKGROUND: Adherence to cardioprotective medications in the year after acute coronary syndrome hospitalization is generally poor and is associated with increased risk of rehospitalization and mortality. Few interventions have specifically targeted this high-risk patient population to improve medication adherence. We hypothesize that a multifaceted patient-centered intervention could improve adherence to cardioprotective medications. METHODS AND RESULTS: To evaluate this intervention, we propose enrolling 280 patients with a recent acute coronary syndrome event into a multicenter randomized, controlled trial. The intervention comprises 4 main components: (1) pharmacist-led medication reconciliation and tailoring; (2) patient education; (3) collaborative care between pharmacist and primary care provider/cardiologist; and (4) 2 types of voice messaging (educational and medication refill reminder calls). Patients in the intervention arm will visit with the study pharmacist ≈1 week post-hospital discharge. The pharmacist will work with the patient and collaborate with providers to reconcile medication issues. Voice messages will augment the educational process and remind patients to refill their cardioprotective medications. The study will compare the intervention versus usual care for 12 months. The primary outcome of interest is adherence using the ReComp method. Secondary and tertiary outcomes include achievement of targets for blood pressure and low-density lipoprotein, and reduction in the combined cardiovascular end points of myocardial infarction hospitalization, coronary revascularization, and all-cause mortality. Finally, we will also evaluate the cost-effectiveness of the intervention compared with usual care. CONCLUSIONS: If the intervention is effective in improving medication adherence and demonstrating a lower cost, the intervention has the potential to improve cardiovascular outcomes in this high-risk patient population.