OBJECTIVE We aimed to assess the influence of CYP2C19*17 on R-warfarin clearance as well as the effect of CYP2C19, CYP2C8, CYP2C9, and VKORC1 polymorphisms together with non-genetic factors on warfarin international normalized ratio (INR)/daily dose. METHODS One hundred fifty Caucasian Italian outpatients with data on steady-state plasma concentrations of S- and R-warfarin were genotyped for CYP2C19 (*2, *3, *4, *17), CYP2C9 (*2, *3), CYP2C8*3, and VKORC1*2. The statistical analysis was performed on the effect of genotypes/haplotypes, age, sex, and body weight on the clearance of warfarin enantiomers and dose-normalized INR. RESULTS R-warfarin clearance was 32% higher in carriers of CYP2C19*17 than in carriers of CYP2C19*2 (mean 2.5 mL/min, 95% confidence interval (CI) 2.3-2.8 vs. 1.9 mL/min, 95% CI 1.7-2.2; P post hoc = 0.01). Patients with CYP2C19*1/*1 genotype had an intermediate clearance (mean 2.1 mL/min, 95% CI 1.8-2.4). The genotypes of VKORC1, CYP2C9, and CYP2C19, together with non-genetic factors (age, sex, and body weight) explained 52% of the variability in warfarin INR/daily dose, of which CYP2C19 genotypes accounted for 7%. CONCLUSIONS This is the first study to include the gain-of-function CYP2C19*17 allele when assessing the impact of CYP2C19 polymorphisms on the clearance of warfarin enantiomers. CYP2C19 genotypes influenced the clearance of R-warfarin and contributed significantly to the variability in INR/daily dose, indirectly indicating a clinical relevance of R-warfarin.