BACKGROUND: Hypothesis-generating data raise the possibility that carriers of the kinesin-like protein 6 (KIF6) 719 arginine (Arg) allele preferentially benefit from statin therapy, and, on this basis, a commercial assay for KIF6 has been developed. METHODS AND RESULTS: In the recently completed JUPITER trial, men and women without prior cardiovascular disease or diabetes who had baseline low-density lipoprotein cholesterol <130 mg/dL and high-sensitivity C-reactive protein ≥ 2 mg/L were randomly allocated to rosuvastatin 20 mg daily or to placebo and followed for first major vascular events (nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, arterial revascularization, or vascular death) and for all-cause mortality. We evaluated the effect of polymorphism at rs20455 encoding the KIF6 719Arg allele on outcomes in this primary prevention trial, both among Caucasian participants and in the trial as a whole. Among 8781 Caucasian trial participants, we observed no increase in vascular event rates among carriers of the KIF6 719Arg allele as compared with noncarriers (hazard ratio, 0.91; 95% confidence interval, 0.66 to 1.26) nor any difference in percent low-density lipoprotein cholesterol reduction with rosuvastatin according to genotype (-52 versus -52 mg/dL, P = 0.11). Rosuvastatin allocation was associated with an almost identical reduction in the trial primary end point among carriers (hazard ratio, 0.61; 95% confidence interval, 0.43 to 0.87) as among noncarriers (hazard ratio, 0.59; 95% confidence interval, 0.39 to 0.88) (P-interaction = 0.90). Genotype had no impact on rosuvastatin efficacy in further analyses that included all-cause mortality, in analyses conducted in the total trial cohort that adjusted for race, or in analyses using generalized models of inheritance rather than recessive models. CONCLUSIONS: In the large primary prevention JUPITER trial, rosuvastatin was equally effective at reducing cardiovascular event rates among carriers and noncarriers of the KIF6 719Arg allele. Thus, at least for rosuvastatin, there appears to be no clinical utility to screening for KIF6 genotype as a method to determine vascular risk or to predict statin efficacy. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681.