An increased loading dose of clopidogrel has been shown to provide more intense and rapid platelet inhibition (PI) than the standard 300-mg dose. However, patient variability in PI and in the timing of platelet recovery may affect efficacy during percutaneous coronary intervention and the bleeding risk of surgery. This study examined the degree of PI after a high-dose load of clopidogrel compared with standard dosing and the time course of functional recovery after the discontinuation of daily therapy. Healthy volunteers (n = 45) were randomized to 3 loading doses of clopidogrel (300, 600, and 900 mg) and continued at 75 mg/day for 6 to 18 days. PI was calculated using a P2Y12-specific point-of-care assay at baseline, hourly for 7 hours after loading, and daily for 5 days after the discontinuation of daily therapy. The groups receiving 600- and 900-mg doses had significantly greater PI than the group receiving the 300-mg dose 2 to 3 hours after loading, but there were no differences between the 600- and 900-mg doses at any time point. Median PI decreased each day after clopidogrel cessation (p < 0.01). On day 5 after discontinuation, the median PI was 12% (interquartile range 0% to 17.4%), but 2 subjects (5%) had persistent PI > 40%. Before day 5, 57% of subjects had recovered platelet function to a PI of < 20%. In conclusion, a 900-mg dose of clopidogrel provides no benefit in terms of magnitude or time to maximal PI compared with a 600-mg dose, but both are superior to a 300-mg dose. A point-of-care assay can identify subjects who may recover platelet function before 5 days after discontinuation or, in contrast, have persistent PI despite discontinuation.