We investigated whether CYP2D6 extensive metabolizers (EM) carrying a non-functional allele are at higher risk of phenoconversion to poor metabolizers in presence of CYP2D6 inhibitors. Seventeen homozygous carriers of two fully-functional alleles and seventeen heterozygous carriers of one fully-functional and one non-functional allele participated in this trial. Dextromethorphan 5mg and tramadol 10mg were given at each of the three study sessions. CYP2D6 was inhibited by duloxetine 60mg (session 2) and paroxetine 20mg (session 3). Higher rate of phenoconversion to IM with duloxetine (71% versus 25%, p=0.009) and to PM with paroxetine (94% versus 56%, p=0.011) was observed in heterozygous than homozygous EMs. The magnitude of drug-drug interaction (DDI) between dextromethorphan and paroxetine was higher in homozygous than in heterozygous subjects (14.6 versus 8.5, p<0.028). Our study suggests that genetic EMs may not represent a homogenous population and that available genetic data should be considered when addressing DDIs in clinical practice. This article is protected by copyright. All rights reserved.