Background Several studies have linked mutations in the genes encoding cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex 1 (VKORC1) to a reduced warfarin dose requirement and an increased risk of bleeding with warfarin treatment, but the implementation of genotyping as routine practice is still controversial. The objective of this study was to investigate whether the frequencies of CYP2C9 variant alleles ( *2 and *3 ), and VKORC1 haplotypes ( *2A/B ) were increased in a population of warfarin-treated patients with an excessive INR response. Methods All patients with INR values >5 detected by routine monitoring at Diakonhjemmet Hospital, Oslo, Norway, between October 2006 and January 2009 were prospectively enrolled in the study ( n  = 131, ‘cases’). A group of patients with normal INR values (2–3) were randomly included as the reference population ( n  = 130, ‘controls’). The frequencies of CYP2C9 variant alleles *2 ( 430C > T ) and *3 ( 1075A > C ), VKORC1 haplotypes *2A ( 1173G > T ) and *2B ( 1173G > T + 497T >G ), and the respective genotypes were compared between the study groups by chi-square tests odds ratio (OR) of cases vs. controls with 95% confidence intervals (CI) calculated for the various end-points. Results About two thirds of the patients in the high INR group were in the maintenance phase of the treatment (>3 weeks from first warfarin dose to measurement of INR >5). The frequency of CYP2C9 variant alleles (sum of   *2 and *3 ) was significantly higher in patients with high INR cases than in the controls (OR 1.6, 95% CI 1.03–2.52; p  = 0.036). Observed frequencies for each of the variant alleles were also higher in the cases than in the controls (i.e., 2C9*3 : OR 1.97, 95% CI 0.91–2.41, p  = 0.073; 2C9*2 : OR 1.36, 95% CI 0.88–1.58, p  = 0.246). There were no significant differences in VKORC1*2 haplotype frequencies between the two subgroups, but the number of homozygous VKORC1*2B carriers was significantly higher in cases than in controls (OR 2.72, 1.02–7.24; p  = 0.039). Conclusion The presence of CYP2C9 variant alleles and the homozygous VKORC1*2B genotype was associated with elevated INR values in warfarin-treated patients. These results support the implementation of genotyping as a tool to identify patients with an increased risk of excessive anticoagulation during warfarin treatment.