Pharmacogenetic dosing improves the accuracy of warfarin dosing, but current pharmacogenetic dosing algorithms are less accurate in populations of African ancestry. The cytochrome P450 2C9*5 (CYP2C9*5) allele is found almost exclusively in populations of African ancestry, and in vitro studies suggest CYP2C9*5 is associated with reduced clearance of warfarin. The clinical relevance of this single-nucleotide variation (SNV) (formerly SNP) is uncertain. In this multicentered study of 2,298 patients (49% female, 35% Black) taking warfarin, we quantified the association between the CYP2C9*5 allele and warfarin requirements. The CYP2C9*5 SNV was present in 2.3% of Black and 0.07% of White patients. Without taking CYP2C9*5 into account, pharmacogenetic algorithms that include other SNVs overestimated the warfarin dose by 30% (95% confidence interval (19–40%), P < 0.001), an average of 1.87 mg/day (SD 1.64) in heterozygotes (P < 0.001). Noncarriers required a slightly (0.23 mg/day, SD 2.09) higher than predicted dose. Genotyping for CYP2C9*5 corrected the potential overdose and halved overall dosing error in heterozygotes. Patients carrying CYP2C9*5 require a clinically relevant reduction in warfarin dose. Given the potential to improve the accuracy and safety of warfarin dosing in populations of African ancestry, we have incorporated this SNV into a nonprofit website to assist warfarin initiation (www.WarfarinDosing.org).