Aim: This study attempted to identify predictors of S-warfarin clearance (CL[S]) and to make a pharmacokinetic evaluation of genotype-based dosing algorithms in African–Americans. Methods: Using plasma S-warfarin concentration (Cp[S]) at a steady state and eight SNPs previously shown to influence warfarin dose in African–Americans, CL(S) and its predictors were estimated by population pharmacokinetic analysis in 60 African–Americans. The time courses of Cp(S) following either the loading dose or maintenance dose were simulated using the population pharmacokinetic estimates. Results: CYP2C9*8 and body surface area or body weight were predictors of CL(S) (-30 and -5% per -0.1 m²/-10 kg reduction in CL[S], respectively) in African–Americans. Simulations of Cp(S) showed that Cp(S) at steady state was 1.4-times higher in patients with CYP2C9*8 than in those with CYP2C9*1/*1, irrespective of the algorithm for loading dose or maintenance dose. Conclusion: African–Americans possess independent predictors of CL(S), possibly leading to a prediction error of any dosing algorithm that excludes African-specific variant(s). Original submitted 3 September 2014; Revision submitted 3 November 2014