We conducted a multi-site investigation of genetic determinants of warfarin dose variability in Latinos from the U.S. and Brazil. Patients from four institutions in the United States (n = 411) and Brazil (n = 663) were genotyped for VKORC1 c.-1639G> A, common CYP2C9 variants, CYP4F2*3, and NQO1*2. Multiple regression analysis was used in the U.S. cohort to test the association between warfarin dose and genotype, adjusting for clinical factors, with further testing in an independent cohort of Brazilians. In the U.S. cohort, VKORC1 and CYP2C9 variants were associated with lower warfarin dose (β = −0.29, P < 2.0 × 10 −16 ; β = −0.21, P = 4.7 × 10 −7 , respectively) whereas CYP4F2 and NQO1 variants were associated with higher dose (β = 0.10, P = 2 × 10 −4 ; β = 0.10, P = 0.01, respectively). Associations with VKORC1 (β = −0.14, P = 2.0 × 10 −16), CYP2C9 (β = −0.07, P = 5.6 × 10 −10), and CYP4F2 (β = 0.03, P = 3 × 10 −3), but not NQO1*2 (β = 0.01, P = 0.30), were replicated in the Brazilians, explaining 43-46% of warfarin dose variability among the cohorts from the U.S. and Brazil, respectively. We identified genetic associations with warfarin dose requirements in the largest cohort of ancestrally diverse, warfarin-treated Latinos from the United States and Brazil to date. We confirmed the association of variants in VKORC1, CYP2C9, and CYP4F2 with warfarin dose in Latinos from the United States and Brazil. Although the use of direct acting oral anticoagulants is increasing, warfarin remains commonly prescribed for prevention and treatment of thromboembolic events. 1,2 Complicating therapy with warfarin is the drug's narrow therapeutic index and high interpatient variability in dose requirements. 3 Latinos are at notably high risk for poor outcomes as a result of nontherapeutic anticoagulation with warfarin. 4-8 Particularly alarming is the increased risk for warfarin-related intracranial hemorrhage in Latinos compared with non-Latino whites. 7 Latinos also have a higher recurrence rate of thrombotic events and worse outcomes from these events compared with whites. 5,