Cytochrome P450 (CYP) 2D6 metabolizes a wide range of xenobiotics and is characterized by a huge interindividual variability. A recent clinical study highlighted differential magnitude of CYP inhibition as a function of CYP2D6 genotype. The aim of this study was to investigate the effect of CYP2D6 genotype on the inhibition of dextromethorphan O-demethylation by duloxetine and paroxetine in human liver microsomes (HLMs). The study focused on genotypes defined by the combination of two fully functional alleles (activity score 2, AS 2, n = 6), of one fully functional and one reduced allele (activity score 1.5, AS 1.5, n = 4) and of one fully functional and one non-functional allele (activity score 1, AS 1, n = 6), which all predict extensive metabolizer phenotype. Kinetic experiments showed that maximal reaction velocity was affected by CYP2D6 genotype, with a decrease in 33% of Vmax in AS 1 HLMs compared to AS 2 (P = 0.06). No difference in inhibition parameters Ki , KI and kinact was observed neither with the competitive inhibitor duloxetine nor with the time-dependent inhibitor paroxetine. Among the genotypes tested, we found no difference in absolute CYP2D6 microsomal levels with ELISA immunoquantification. Therefore, our results suggest that genotype-sensitive magnitude of drug-drug interactions recently observed in vivo is likely to be due to differential amounts of functional enzymes at the microsomal level rather than to a difference in inhibition potencies across genotypes, which motivates for further quantitative proteomic investigations of functional and variant CYP2D6 alleles.