558 Background: Tamoxifen is a selective estrogen receptor modulator (SERM) that is commonly used to treat breast cancer. However, despite its established efficacy, recent studies indicate that 1) more than 50 percent of individuals will discontinue treatment prior to completing the recommended five-year therapeutic regimen and 2) the likelihood of discontinuation is moderated by the presence of polymorphisms in the gene encoding cytochrome P450 2D6 (CYP2D6), the enzyme responsible for metabolizing tamoxifen into its active form. Methods: We measured tamoxifen persistency rates in a cohort of breast cancer patients to test the hypothesis that tamoxifen adherence is modified by the dose administered and concomitant use of anti-depressant (SSRI) drugs known to interfere with CYP2D6 metabolism. Study subjects (N = 12,742) were identified in a large transactional claims database, cross-classified by tamoxifen dose (HIGH, NORMAL) and SSRI status (YES, NO), and followed for 360 days after initiation of therapy. Results: Cox regression was used to generate covariate-adjusted hazard ratios and 95% confidence intervals for each treatment combination [NORMAL/YES = 1.17 (1.10, 1.24); HIGH/YES = 2.38 (1.86, 3.049); HIGH/NO = 3.27 (2.86, 3.74)] relative to the reference group (NORMAL/NO). The results indicate that patients who receive a high dose of tamoxifen are more likely to discontinue therapy than patients who receive the standard regimen. Moreover, CYP2D6 inhibitor drugs (SSRI) significantly improve medication adherence when prescribed in concert with a high dose of tamoxifen. Both findings are consistent with the observation that CYP2D6 extensive (vs. poor) metabolizers are less likely to tolerate a high dose of tamoxifen and, thus, more likely to discontinue therapy before the drug's protective benefits are realized. Conclusions: The study highlights the need for education and research regarding tamoxifen dosing and careful consideration for when SSRI medications should be prescribed to enhance patient tolerance of tamoxifen-related side effects. The results may also support a role for CYP2D6 genotyping in the context of tamoxifen-based treatment of breast cancer. No significant financial relationships to disclose.