Background: Tamoxifen treated breast cancer patients with diminished CYP2D6 activity have lower endoxifen exposure, which may lead to inferior treatment outcomes. Increasing the daily tamoxifen dose from 20 mg to 40 mg increases endoxifen in CYP2D6 poor (PM) and intermediate (IM) metabolizing patients. We previously reported that endoxifen exposure of an IM pt receiving 40 mg is similar to that of an extensive or ultra-rapid metabolizer (EM/UM) receiving 20 mg, while a PM at 40 mg continues to have lower exposure. Here we investigated whether increasing the dose to 40 mg/day in CYP2D6 PM and IM increases treatment toxicity. Methods: Patients receiving 20 mg tamoxifen for ≥ 4 months who were not taking a strong CYP2D6 inhibitor were genotyped for CYP2D6 using the Amplichip CYP450 test (Roche Diagnostics, Indianapolis, IN). PM and IM were increased to 40 mg for 120 days while EM/UM remained on 20 mg. Toxicity data was collected on the ordinal FACT-B Endocrine Subscale (0: “not at all” to 4 “very much”) at enrollment and 120 days. The prevalence of patients reporting any toxicity ≥ 3 (“quite a bit”) and the rating (0-4) of specific toxicities were compared across CYP2D6 phenotypes. Results: Of the 484 evaluable patients, 29 were PM, 293 IM and 162 EM/UM. At enrollment (all receiving 20 mg) there was a non-significant trend toward greater prevalence of toxicity as CYP2D6 activity increased (PM=55.2%, IM=57.0%, EM/UM=62.4%, p=0.25) with a significantly higher rating of vaginal dryness (PM=0.76, IM=0.84, EM/UM=1.06, p=0.03) but not hot flashes (p=0.80). After 120 days of 40 mg treatment there was a significant increase in the prevalence of toxicity in IM (change from baseline= +7.4%, p<0.001), but not PM (change=-11.7%, p=0.71). There was no significant increase in the rating of any toxicity (p>0.05). Conclusions: Increasing the daily tamoxifen dose in CYP2D6 IM, but not PM, is associated with a corresponding increase in global toxicity that cannot be attributed to any single toxicity. Analysis as to whether this impacts patients’ QOL is ongoing. Given the absence of known impact on outcomes, increasing the tamoxifen dose should be discouraged in patients with diminished CYP2D6 activity. Clinical trial information: NCT00764322.