WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT * CYP2C9 and VKORC1 genetic variants contribute to differences in patients' responses to anticoagulant coumarin derivatives. Patients carrying the VKORC1 1173TT genotype have a decreased time to the first INR within the therapeutic range and to the first INR >4, and also require lower warfarin maintenance doses. Patients carrying the *2 or *3 CYP2C9 allele have lower maintenance warfarin requirements than those carrying the wild-type allele. The role of CYP2C9 and VKORC1 genetic variants in fluindione response is unknown. WHAT THIS STUDY ADDS * Our results showed that VKORC1 genotype had a significant impact on early anticoagulation (INR value ≥2 after the first two intakes) (P < 0.0001), on the time required to reach a first INR within the therapeutic range (P < 0.0001), on the time to obtain a first INR value >4 (P= 0.0002) and on the average daily dose of fluindione during the first period of stability (19.8 mg (±5.5) for VKORC1 CC, 14.7 mg (±6.2) for VKORC1 CT and 8.2 mg (±2.5) for VKORC1 TT, P < 0.0001). CYP2C9, CYP4F2 and EPHX1 genotypes did not significantly influence the response to fluindione. This report provides new information on the respective role of common genetic polymorphisms on anticoagulation induced by another class of anticoagulant drugs rather than coumarin derivatives. AIM Genetic variants of the enzyme that metabolizes warfarin, cytochrome P-450 2C9 (CYP2C9) and of a key pharmacologic target of vitamin K antagonists, vitamin K epoxide reductase (VKORC1), contribute to differences in patients' responses to coumarin derivatives. The role of these variants in fluindione response is unknown. Our aim was to assess whether genetic factors contribute to the variability in the response to fluindione. METHODS Four hundred sixty-five patients with a venous thromboembolic event treated by fluindione for at least 3 months with a target international normalized ratio (INR) of 2.0 to 3.0 were studied. VKORC1, CYP2C9, CYP4F2 and EPHX1 genotypes were assessed. INR checks, fluindione doses and bleeding events were collected. RESULTS VKORC1 genotype had a significant impact on early anticoagulation (INR value ≥2 after the first two intakes) (P < 0.0001), on the time required to reach a first INR within the therapeutic range (P < 0.0001) and on the time to obtain a first INR value > 4 (P= 0.0002). The average daily dose of fluindione during the first period of stability was significantly associated with the VKORC1 genotype: 19.8 mg (±5.5) for VKORC1 CC, 14.7 mg (±6.2) for VKORC1 CT and 8.2 mg (±2.5) for VKORC1 TT (P < 0.0001). CYP2C9, CYP4F2 and EPHX1 genotypes did not significantly influence the response to fluindione. CONCLUSIONS VKORC1 genotype strongly affected anticoagulation induced by fluindione whereas CYP2C9, CYP4F2 and EPHX1 genotypes seemed less determining.