Background: An assessment of how panels of single-nucleotide polymorphism (SNP) breast cancer risk factors might improve risk assessment among high-risk women is needed for better targeting of preventive therapy and other risk reduction measures. Methods: A case-control study was designed using leukocytic or tissue DNA from two tamoxifen prevention trials (IBIS-I and Marsden). SNPs were assayed on the Sequenom platform and a relative risk score for 15 SNPs (SNP15) was formed using the most recent iCOGS SNP risk estimates. Baseline questionnaires were used to estimate 10-year relative risks from the Tyrer-Cuzick model (TC). Conditional logistic regression was used to assess performance. An updated panel using all validated risk SNPs (approx. 70) is also being evaluated and will be presented at the meeting. Results: 440 cases and 686 controls had median age at baseline of 49 (inter-quartile range 45 - 54). Hardy-Weinberg equilibrium was verified. SNP15 and TC appeared uncorrelated (Spearman 0.037, P=0.209). The odds ratio (OR) between 25^th, 75^th percentiles of SNP15 was 1.24 (95% CI 1.05 - 1.46) with AUC 0.568; TC had OR 1.41 (1.21 - 1.64), AUC 0.578; combined OR 1.54 (1.30 - 1.83), AUC 0.600. The observed risk was 48% (11 – 84) of predicted for SNP15 and 77% (42 – 110) for TC. SNP15 was more predictive for estrogen receptor (ER) positive tumours (318 cases, OR 1.36 (1.12 – 1.64), AUC 0.587, 67% (25-109) of predicted) but not for estrogen-receptor (ER) negative cancer (122 cases, P = 0.76); TC was significantly associated with both ER types. Little difference in performance was seen between tamoxifen and placebo treatment arms. The proportion of untreated women with 10-yr predicted risk above 8% was <1% for SNP15, 18% for TC and 25% for the combined risk score. Conclusions: A SNP panel is useful for refining risk estimates in women with phenotypic risk factors for breast cancer, and adds important information to classic phenotypic factors but does not appear to vary according to potential to benefit from tamoxifen. Clinical trial information: ISRCTN91879928 (ref: CCT-NAPN-14839).