OBJECTIVES:  In patients with acute coronary syndromes (ACS), continued treatment with thienopyridine regimens has been associated with fewer major adverse cardiac events. In the TRITON-TIMI 38 trial, prasugrel was compared to clopidogrel in ACS patients undergoing percutaneous coronary intervention (PCI) resulting in a 19% reduction in cardiovascular death, myocardial infarction, or stroke, but an increase in TIMI defined bleeding (10.9% vs 7.9%, p<0.001). The impact of these complications on medication persistence and adherence is unknown.  The objective of this study was to compare persistence and adherence of clopidogrel and prasugrel in TRITON TIMI-38.  METHODS:  TRITON TIMI-38 was a double-blind, randomized, controlled trial which enrolled 13,608 patients with ACS and planned PCI.  Of the 13,608 patients enrolled, 13,457 patients received at least one dose of study drug and were evaluated for this study. Patients treated with prasugrel (N=6,741) or clopidogrel (N=67,16) were followed for up to 15 months.  Adherence was calculated using the medication possession ratio (MPR), the total days with medication divided by total days in the study. Persistence was measured as the time from randomization to the first gap of >14 days between exhausting the supplied medication and filling the next prescription. Sensitivity analyses using gaps of 7 and 30 days were performed.  Clopidogrel and prasugrel adherence and persistence were compared using multivariate linear regression, controlling for demographics and illness history. Robustness of results was examined using alternative modeling. RESULTS:  A total of 17.6% of patients prematurely discontinued study drug (prasugrel, 17.9% vs. clopidogrel, 17.3%, p=0.382). The MPR for prasugrel (0.96) and clopidogrel (0.96) were similar (p=0.801). Similar persistence levels between prasugrel-treated patients and clopidogrel-treated patients were observed using the 14-day gap (319 vs. 322 days, p=0.296). Sensitivity analysis using 7-day and 30-day gaps confirmed these findings.  Study drug was discontinued for a hemorrhagic adverse event (AE) in 2.5% of prasugrel patients compared to 1.4% of clopidogrel patients (p<0.001) and stopped for a non-hemorrhagic AE in 4.6% v 5.0% (p=0.372). CONCLUSIONS:  Despite an increase in TIMI defined bleeding and an increased rate of discontinuation of study drug for a hemorrhagic event with prasugrel, similar levels of adherence and persistence were observed for prasugrel-and clopidogrel-treated ACS patients with PCI in TRITON TIMI-38. Further study will be necessary to determine whether these results can be replicated outside of the clinical trial setting.