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Warfarin is a widely used anticoagulant whose activeS-enantiomer is primarily metabolized by the CYP2C9 enzyme. TheCYP2C9*2andCYP2C9*3 alleles are associated with lower warfarin dose requirement and decreased enzyme activity. In contrast, we previously identified a novel single-nucleotide polymorphism (SNP) (rs7089580A > T) inCYP2C9that is associated with higher warfarin dose requirement in African Americans (AAs). In this study, we examine the effect of rs7089580 on warfarin pharmacokinetics andCYP2C9expression in 63 AA patients and 32 AA liver tissues, respectively. We found oral clearance ofS-warfarin to be higher among carriers of the minor rs7089580 allele (T) compared with wild-type homozygotes (3.73 ± 1.46 vs 2.95 ± 1.39 mL/min;P= 0.04).CYP2C9messenger RNA expression in liver tissue was also higher among A/T and T/T genotypes compared with A/A (P< 0.02). Our findings indicate that rs7089580 is associated with higherS-warfarin clearance andCYP2C9expression and may help explain the higher dose requirement of warfarin in AAs. Furthermore, rs7089580 is in complete linkage disequilibrium with the promoter SNP rs12251841 in AAs, which may provide a biologically plausible explanation for the observed effect onCYP2C9expression levels. Given the many clinically relevant substrates of CYP2C9, identifying polymorphisms that affect expression levels and metabolism across ethnicities is essential for individualization of doses with a narrow therapeutic index.