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Well‐characterized genes that affect warfarin metabolism (cytochrome P450 (CYP) 2C9) and sensitivity (vitamin K epoxide reductase complex 1 (VKORC1)) explain one‐third of the variability in therapeutic dose before the international normalized ratio (INR) is measured. To determine genotypic relevance after INR becomes available, we derived clinical and pharmacogenetic refinement algorithms on the basis of INR values (on day 4 or 5 of therapy), clinical factors, and genotype. After adjusting for INR, CYP2C9 and VKORC1 genotypes remained significant predictors (P < 0.001) of warfarin dose. The clinical algorithm had an R² of 48% (median absolute error (MAE): 7.0 mg/week) and the pharmacogenetic algorithm had an R² of 63% (MAE: 5.5 mg/week) in the derivation set (N = 969). In independent validation sets, the R² was 26–43% with the clinical algorithm and 42–58% when genotype was added (P = 0 …