Background: Capecitabine is an effective therapy for advanced breast cancer; however, response prediction is imprecise. In this study, we aimed to identify potential SNPs associated with response in MBC pts treated with capecitabine. Methods: Women with MBC about to receive single-agent capecitabine were enrolled and then dosed at 2000 mg/m²/day for 14 d on/7 d off, until unacceptable toxicity or disease progression. Pts were assessed by RECIST criteria. Primary analysis was a genome-wide association study (GWAS) analysis conducted with best response during treatment (PD vs. PR/CR) and stratified for the presence of liver metastases (mets) and estrogen receptor (ER) status. Genotyping was performed on the Illumina Human OmniExpress chip. Analysis was restricted to Caucasian pts to remove confounding by population stratification. Results: 258 pts from 14 institutions were enrolled. Pt characteristics included median age 57 yrs (range 25-85), 47.4% with liver mets and 74% were ER+. 30 pts were excluded due to incomplete response data. Final analysis was conducted on 136 Caucasian pts. Response was as follows: 4 (1.9%) CR, 27 (13.1%) PR, 104 (50.4%) SD, 71 (34.4%) PD. While no SNPs reached genome-wide significance ( < 6.9 x 10^-8), top GWAS signals included a novel SNP upstream of BP1FB2 (p = 0.0007, OR 27.6), an intronic variant SNP in ADAMTS3 (p = 0.0007, OR = 51.6), and an intronic variant in Wnt7a (p = 0.0009, OR 28.4) as associated with response to capecitabine treatment. Wnt7a has been shown to promote tumor aggressiveness through fibroblast activation, and ADAMTS3 is downregulated in breast cancer compared to normal mammary tissue. BP1FB2 has not been previously implicated in breast cancer. Conclusions: We identified several promising markers of disease response in women with MBC treated with capecitabine. Although these SNPs did not achieve genome-wide significance and may be due to false discovery, further investigation is merited to discern whether Wnt7A and ADAMTS3 are merely markers of aggressive MBC or have a more specific role in influencing capecitabine response. Clinical trial information: NCT00977119