Purpose Capecitabine is a widely used 5-fluorouracil oral prodrug. Hand-foot syndrome (HFS), one of the most common adverse events of capecitabine, impacts patients' quality of life seriously. The pathogenesis of HFS remains unclear but was usually considered as a type of inflammation conducted by cyclooxygenase-2 (COX-2). The COX-2/PGES/EP signaling pathway plays an important role in the inflammatory reaction. We hypothesized that the single nucleotide polymorphisms (SNPs) in this pathway may be associated with the risk of HFS induced by capecitabine. Patients and methods Using DNA from blood samples of 225 patients, we genotyped 19 SNPs in 6 core genes (COX-2, PGES, EP1, EP2, EP3, and EP4). Common Terminology Criteria for Adverse Events version 3.0 was used to grade hand-foot syndrome. We used logistic regression analysis to evaluate the correlations between genotype variants and occurrence of HFS. The cumulative incidence of HFS was assessed by Kaplan-Meier analysis. Results Among the 225 participants, 58.6% (132/225) patients developed into HFS, including 41.3% (93/225) grade 1 HFS, 10.2% (23/225) grade 2 HFS and 7.1% (16/225) grade 3 HFS. Multivariate logistic regression analysis showed the AG/GG genotype of rs3810255 to be associated with a significantly higher risk of grade 2/3 HFS, while the AG/AA genotype of rs17131450 to be associated with a significantly lower risk of grade 2/3 HFS (OR = 3.646, P = 0.011; and OR = 0.266, P = 0.036; respectively). Conclusion Our study showed that rs3810255 AG/GG genotypes and rs17131450 GG genotypes to be associated with high risk of capecitabine-induced HFS.