Background: Tamoxifen (TAM) is transformed via CYP2D6 to its major active metabolite endoxifen (Endox). Recent data suggest that 15nM Endox may be a therapeutic threshold for breast cancer. This study identified predictors of achieving specified Endox target levels (15nM and 30nM) on standard dose TAM, and following dose escalation. Methods: Baseline Endox was measured in 122 breast cancer pts on TAM 20mg pd. Pts with baseline Endox <30nM underwent incremental dose escalation to a maximum of 60mg pd until Endox reached 30nM or dose limiting toxicity. Clinical data were collected and CYP2D6 genotype was used to specify extensive, intermediate or poor metabolizer categories (EM, IM, PM). Multiple regression analyses examined associations between Endox and potential predictive factors. Results: Baseline Endox ranged from 3.1-72.2nM (mean 27.6nM). In 19% (n=23), baseline Endox was below 15nM and 62% (n=76) were below 30nM. Low baseline Endox was associated with CYP2D6 genotype (IM or PM, p<0.001) and younger age (p=0.02). Following dose escalation, 96% (n=117) attained an Endox level of 15nM and 76% (n=93) reached 30nM. Baseline Endox level was the only variable independently associated with achieving both targets (p=0.02, p<0.001 respectively). CYP2D6 genotype did not independently predict attainment of Endox targets following dose escalation (p>0.4). The ratio of Endox to its precursor N-desmethylTAM, an indicator of CYP2D6 activity, was stable with dose escalation, suggesting that CYP2D6 was not saturated. Conclusions: Although IM/PM predict for low Endox on 20mg TAM, only low baseline Endox predicted failure to achieve both 15nM and 30nM targets following dose escalation. These results suggest a role for Endox level monitoring to determine optimal TAM dose. Clinical trial information: NCT01075802.