Failure to achieve an adequate level of platelet inhibition during percutaneous coronary intervention is associated with an increased risk for periprocedural myocardial injury. This study was conducted to compare the initial rate of platelet inhibition after a loading dose (LD) of prasugrel or clopidogrel and determine the association between the initial rate of inhibition and pharmacodynamic responder status. Data were pooled from 3 studies in which healthy subjects received LDs of prasugrel (60 mg; n = 76) or clopidogrel (300 mg; n = 87). Maximum platelet aggregation (MPA; 20 mumol/L adenosine diphosphate) was measured by turbidimetric aggregometry (0.25 to 24 hours after dosing). A mechanistic model was used to estimate the initial rate of decrease in MPA per hour (fast onset: MPA decrease >20%/hour). Subjects were defined as pharmacodynamic poor responders if the absolute decrease in MPA from baseline was <15% at either 4 to 5 or 24 hours after dosing. The median initial rate of decrease in MPA was greater after prasugrel (203%/hour) than with clopidogrel (23%/hour) (p <0.001). Overall, 76 subjects (100%) receiving prasugrel had fast onset of platelet inhibition compared with 47 subjects (54%) receiving clopidogrel. The initial rate of decrease in MPA was highly correlated with responder status (p <0.001). After prasugrel, subjects had a lower median MPA compared with clopidogrel (p <0.001; from >0.25 to 24 hours after dosing), and intersubject variability in MPA response was less after prasugrel compared with clopidogrel (p <0.001; from >1 to 24 hours after dosing). In conclusion, platelet inhibition after a 60-mg LD of prasugrel was more rapid in onset, less variable, and greater in magnitude than with a 300-mg LD of clopidogrel. After a thienopyridine LD, the initial rate of platelet inhibition was predictive of pharmacodynamic responder status.