Further multivariate unconditional logistic regression analysis indicated that the genotype AG of MTHFR rs3737964 (OR = 0.54, 95% CI 0.31–0.97, P = 0.038) and MTHFR rs4846048 (OR = 0.54, 95% CI 0.30–0.98, P = 0.042) were protective factors for HFS. Here, MTHFR is linked to Hand-foot syndrome.