Acenocoumarol (AC) is a coumarin derivative, vitamin K antagonist, used in the anticoagulant therapy, having a narrow therapeutic index and a large pharmacokinetic and pharmacodynamic interindividual variability. This variability is due to genetic polymorphisms in the enzymes and transporters participating in its metabolism. Aim: To investigate the association between the AC dose requirements for achieving a target level of anticoagulation and allelic variants in the gene products are associated with its metabolism and transport: CYP2C9*2 and *3; CYP1A2*1F; CYP2C19*2 and CYP2C19*3; CYP3A4*1B; CYP3A5*3; MDR1 A61>G, MDR1 G2677>T and MDR1 C3435>T. Study design and methods: Our study included 119 Bulgarian patients treated with the oral anticoagulant AC for at least 3 months. They were separated in four groups according to their AC dose requirement: very low, low, medium and high. For detection of studied polymorphic variants a real time PCR was used. Results: CYP2C9 genotypes distribution analysis showed that the carriers of CYP2C9*1/*3, CYP2C9*2/*2 CYP2C9*2/*3 genotypes are more prevalent in the group of very low dose requirement of AC compared to the other three groups (?2=26.64, df=12, p= 0.009). The frequency of wild type genotype CYP2C9*1/*1 was predominant in the group of patients with high dose requirements (81.8%), compared to that in the groups of medium, low and very low dose requirements (64.7%, 61.3% and 26.7%). The distribution of other polymorphisms did not show significant difference between the four groups. Conclusion: The carriership of CYP2C9*2 or/and CYP2C9*3 allele in Bulgarian patients is associated with low dose requirement of AC.