IMPORTANCE Despite guideline recommendations, many patients discontinue P2Y 12 inhibitor therapy earlier than the recommended 1 year after myocardial infarction (MI), and higher-potency P2Y 12 inhibitors are underutilized. Cost is frequently cited as an explanation for both of these observations. OBJECTIVE To determine whether removing co-payment barriers increases P2Y 12 inhibitor persistence and lowers risk of major adverse cardiovascular events (MACE). DESIGN, SETTING, AND PARTICIPANTS Cluster randomized clinical trial among 301 hospitals enrolling adult patients with acute MI (June 5, 2015, through September 30, 2016); patients were followed up for 1 year after discharge (final date of follow-up was October 23, 2017), with blinded adjudication of MACE; choice of P2Y 12 inhibitor was per clinician discretion. INTERVENTIONS Hospitals randomized to the intervention (n = 131 [6436 patients]) provided patients with co-payment vouchers for clopidogrel or ticagrelor for 1 year (median voucher value for a 30-day supply, $137 [25th-75th percentile, $20-$339]). Hospitals randomized to usual care (n = 156 [4565 patients]) did not provide study vouchers. MAIN OUTCOMES AND MEASURES Independent coprimary outcomes were patient-reported persistence with P2Y 12 inhibitor (defined as continued treatment without gap in use Ն30 days) and MACE (death, recurrent MI, or stroke) at 1 year among patients discharged with a prescription for clopidogrel or ticagrelor. RESULTS Among 11 001 enrolled patients (median age, 62 years; 3459 [31%] women), 10 102 patients were discharged with prescriptions for clopidogrel or ticagrelor (clopidogrel prescribed to 2317 [36.0%] in the intervention group and 2497 [54.7%] in the usual care group), 4393 of 6135 patients (72%) in the intervention group used the voucher, and follow-up data at 1 year were available for 10 802 patients (98.2%). Patient-reported persistence with P2Y 12 inhibitors at 1 year was higher in the intervention group than in the control group (unadjusted rates, 5340/6135 [87.0%] vs 3324/3967