Background: Breast cancer is a global problem, and 1.7 million new cases are diagnosed per year. Capecitabine, an oral prodrug of fluorouracil, has been reported to be effective in patients with metastatic breast cancer (MBC) and approved by the Unites States Food and Drug Administration for treatment of MBC. Hand-foot syndrome (HFS) is one of the most relevant dose-limiting adverse effects of capecitabine. If HFS is not handled well, it can deteriorate rapidly and lead to the treatment interruptions which may influence on the treatment efficacy. Methods: In our study, we investigated the association between single nucleotide polymorphism (SNP) and capecitabine-based HFS in patients with MBC in Chinese Han population, in an attempt to identify some predictive genetic biomarkers. We selected 3 genes involved in capecitabine metabolism and screened genetic variants in the target genes. We genotyped a total of 22 SNPs in the thymidylate synthase gene (TYMS), the methylene tetrahydrofolate reductase gene (MTHFR) and the ribonucleotide reductase M1 gene (RRM1) in 342 patients treated with capecitabine-based chemotherapy. Results: Logistic regression analyses showed that genotype AG of rs3737964 [odds ratio (OR) = 0.54,95% confidence interval (CI) = 0.31-0.97, P = 0.038] and genotype AG of rs4846048 (OR = 0.54,95%CI = 0.30-0.98,P = 0.042) in MTHFR were protective factors for HFS. That was to say, patients with these two kinds of genotypes in the Chinese Han population might have 0.54-fold lower risk of suffering from HFS. Genotype GT of rs2606241 (OR = 1.27,95%CI = 0.73-2.23,P = 0.012) and genotype CT of rs2853741 (OR = 2.25,95%CI = 1.31-3.87,P = 0.012) in TYMS increased the incidence of HFS. Patients with genotype GT of rs2606241 and genotype CT of rs2853741 were found to have 1.27-fold and 2.25-fold higher risk of suffering from HFS. Conclusions: In summary, we have identified a panel of clinically useful pharmacogenetic markers predicting capecitabine-induced HFS in MBC patients.