Background: C is associated with sometimes severe tox affecting patient (pt) adherence and quality of life, which can result in dose disruption/reduction potentially attenuating effectiveness. We sought to identify pharmacogenomic (PGx) markers of C tox using a novel prospective tox assessment method in a large, multi-institutional study of women with MBC. Methods: Pts were prospectively identified prior to C monotherapy initiation at 2000 mg/m²/d, 14 d on/7 off. Pts completed in-person tox questionnaires (q) on d1 of each cycle (cy) and automated phone-in q on d8, d15 for 4 cy, but met study endpoint earlier if C was dose-reduced or suspended. Genetic analysis of 50 prespecified markers and a separate genome-wide association study (GWAS) were conducted with phenotypes immediate (cy 1) and overall diarrhea or hand-foot syndrome (HFS). Results: N = 259 pts enrolled from 14 institutions (median age 57 yrs, range 25-85). Pt adherence with tox reporting was robust, with 86% (cy 1) and 71% (cy 4) of q completed. Rates of any-grade diarrhea and HFS were 52% and 69%, respectively, including 17% reporting grade 3 diarrhea and 9% grade 3 HFS. Worst tox was identified solely via at-home phone reporting in 39% of pts. Only 29% of pts completed 4 cy without C interruption, dose change, or early discontinuation. In candidate PGx analysis, 3 SNPs associated with development of diarrhea: DPYD*5 (OR 4.9; P = 0.0005, significant after multiple test correction), missense SNP in MTHFR (OR 3.3; P = 0.02), and upstream SNP of MTRR (OR 3.0; P = 0.03). For HFS, GWAS elucidated a novel SNP (OR 3.0; P = 0.0007) upstream of TNFSF4, a gene implicated in systemic sclerosis and graft-versus-host disease of skin, never before implicated in HFS. Conclusions: To our knowledge, this is the first PGx study to use phone-in pt self-reporting, permitting increased accuracy of tox-phenotype characterization. Three germline SNPs previously associated with fluorouracil sensitivity in preclinical/clinical models were identified, and a novel SNP having strong functional relevance was discovered. If further replicated, these markers could improve prediction of pts at highest risk for C tox, reducing morbidity and enhancing outcomes. Clinical trial information: NCT00977119