Background: Anthracycline-induced congestive heart failure (CHF) is a rare but serious toxicity associated with this commonly employed anti-cancer therapy. The ability to predict which patients might be at increased risk prior to exposure would be valuable to optimally counsel risk to benefit ratio for each patient. Herein we present a genome wide approach for biomarker discovery with two validation cohorts to predict CHF from adult patients planning to receive an anthracycline. Methods: We performed a genome wide association study (GWAS) in 3431 patients from the randomized phase III adjuvant breast cancer trial E5103 to identify SNP genotypes associated with an increased risk of anthracycline-induced CHF. We further attempted candidate validation in two independent phase III adjuvant trials, E1199 and BEATRICE. Results: When evaluating for cardiologist adjudicated CHF, 11 SNPs had a p-value <10^-5 of which 9 independent chromosomal regions were associated with increased risk. Validation of the 2 top SNPs in E1199 revealed one SNP, rs28714259 that demonstrated a borderline increased CHF risk (p=0.04, OR=1.9). rs28714259 was subsequently tested in BEATRICE and was significantly associated with a decreased left ventricular ejection fraction (p=0.018, OR=4.2). Combining results from these independent studies provided further evidence of a significant association between rs28714259 and cardiac damage (p=7.4 x10^-9). Conclusions:rs28714259 represents a validated SNP that is associated with anthracycline-induced CHF in three independent, phase III adjuvant breast cancer clinical trials.