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The present study aimed to explore the influence of sirtuin 1 (SIRT1) polymorphisms (rs12778366 and rs3758391) on diabetic foot (DF) susceptibility and severity in patients with type 2 diabetes mellitus (T2DM).This case–control study recruited 142 patients with DF, 148 patients with T2DM, and 148 healthy controls. SIRT1 gene polymorphisms were sequenced by polymerase chain reaction (PCR) and direct sequencing method. The relative expression of SIRT1 mRNA was estimated using quantitative real-time PCR (qRT-PCR) assay. Odds ratio (OR) with 95% confidence interval (95% CI) were used to represent the association of SIRT1 polymorphisms with DF susceptibility and severity. The results were adjusted using logistic regression analysis.C allele of rs12778366 polymorphism was significantly correlated with reduced DF susceptibility which deriving from healthy controls (adjusted OR = 0.364, 95% CI = 0.158–0.835) so was patients with T2DM (P = .047, OR = 0.591, 95%CI = 0.349–0.998), but the results became nonsignificant adjusted by clinical features (adjusted OR = 0.654, 95% CI = 0.391–1.094). We failed to find any significant association between rs3758391 polymorphisms and T2DM, DF susceptibility. No significant association has been discovered between SIRT1 polymorphisms and DF severity or characteristics. In addition, compared to healthy control and T2DM cases, patients with DF exhibited significant downregulation of SIRT1. The 2 studied polymorphisms had no effects on its gene expression (P > .05 for all).SIRT1 rs12778366 polymorphism C allele might act as a protective factor for DF onset.