Background: Commonly occurring genetic variants in CYP2C9 are known to reduce catalytic activity and are associated with enhanced patient sensitivity to warfarin. Interethnic differences in warfarin dose requirement have been described in the Asian population, and we postulate that this could be related to genetic variants of CYP2C9 that are unique to ethnic groups. Methods: We prospectively genotyped 125 patients who were receiving a stable daily warfarin dose to maintain international normalized ratio values between 2 and 3 through comprehensive sequencing of the promoter and coding regions of the CYP2C9 gene. Results: The mean weight-adjusted warfarin maintenance dose was significantly lower for Malay and Chinese subjects than Indian subjects (P<.001 and. 014, respectively). Warfarin dose negatively correlated with age (r=-0.4, P<.001) but not with sex. Multiple variants were detected in the promoter, exonic, intronic, and 3=-untranslated regions of CYP2C9, of which 16 were novel, including 7 nonsynonymous exonic variants (208G>C, 374G>A, 485C>A, 895A>G, 1144C>T, 1190A>C, and 1362G>C). CYP2C9*3, but not CYP2C9*2, was found in Chinese and Malay patients, and carriers of the CYP2C9*3 variant in Chinese (P<.01) and Indian (P<.01) patients, but not Malay patients (P=.77), required less warfarin. The influence of the novel exonic variants on warfarin dose requirement was unclear, because they were rare, but the lower warfarin dose requirement for Chinese and Malay patients existed despite omission of individuals with any coding region variants from analysis. Conclusions: Interethnic differences in warfarin dosing in Asian subjects may result from other genetic, dietary, or environmental influences; however, these novel variants in the gene warrant further characterization through functional studies. (Clin Pharmacol Ther 2004; 76:210-9.)