Background: Genetic polymorphisms leading to reduced CYP2D6 activity and the use of CYP2D6 inhibitors both influence the formation of endoxifen (active metabolite of tamoxifen (TAM)). CYP2D6 genotyping is not part of the standard clinical management of patients treated with TAM and there are no formal recommendations for dose adjustments in patients using TAM and a CYP2D6 inhibitor. We hypothesized that in patients who are either a CYP2D6 intermediate or poor metabolizer and/or are treated with a CYP2D6 inhibitor a dose adjustment of TAM compensates for reduced formation of endoxifen. Methods: Female breast cancer patients treated with TAM 20mg QD for at least 4 weeks were included. They were genotyped for CYP2D6 variant alleles (inactive alleles *3, *4, *5, *6 and decreased activity alleles *10, *41). Patients with at least one inactive allele, two decreased CYP2D6 activity alleles, and/or concomitant use of a CYP2D6 inhibitor received a dose increase of TAM to 40mg QD for 4 weeks. TAM, 4-OH-TAM, N-desmethylTAM and endoxifen levels were determined with LC-MS in blood samples at screening and after 4 weeks. Results: 40 patients with median age 55 (range 37-81) years were enrolled of which 22 extensive (EM), 15 intermediate (IM) and 3 poor metabolizers (PM) for CYP2D6. Three EMs concomitantly used a CYP2D6 inhibitor (paroxetine, escitalopram or citalopram) and were categorized as PM. Mean (SD) endoxifen levels in EMs, IMs, and PMs were 11.4 (5.2), 8.7 (4.6) and 4.1 (1.4) ng/mL, respectively (one-way ANOVA: p=0.007). Three patients were genotyped as *4/*41 or *41/*41, and by consensus classified as IMs; their endoxifen levels (1.9; 3.4; 3.7 ng/mL, respectively) were, however, not different from those observed in PMs. 10 patients have completed the 4 week dose increase (8 IMs, 2 PMs). Mean endoxifen level for the IMs increased from 10.3 to 17.0 ng/mL and from 3.0 to 5.4 ng/mL in the PMs. No serious adverse events occurred after the dose increase. Conclusions: Increasing the dose of TAM from 20 mg to 40 mg QD can compensate for the reduced endoxifen level in CYP2D6 IMs. In contrast, a dose increase to 40mg QD in PMs does not appear to be sufficient to reach endoxifen levels seen in EMs.