Variation in patient response to antiplatelet therapy with clopidogrel occurs because of genetic polymorphisms that affect drug metabolism. In the randomized PHARMCLO trial, a pharmacogenomic approach to tailoring antiplatelet therapy (clopidogrel, prasugrel, or ticagrelor) on the basis of ABCB1, CYP2C19*2, and CYP2C19*17 genotype was compared with standard care. A total of 888 patients with acute coronary syndrome were enrolled before the trial was prematurely stopped. Clopidogrel was used more in the standard-care group, ticagrelor was used more in the pharmacogenomic group, and prasugrel was used equally in each group. During 12 months of follow-up, the rate of the primary composite end point (cardiovascular death or the first occurrence of nonfatal myocardial infarction, nonfatal stroke, or major bleeding) was lower in the pharmacogenomic group than in the standard-care group (15.9% versus 25.9%; HR 0.58, 95% CI 0.43–0.78, P < 0.001), indicating that personalized therapy might reduce the rate of ischaemic and bleeding events.