Abstract: Objective To research the correlation between substance P (SP) of serum neuropeptide and diabetic foot in diabetic patients, and to make early diagnosis and clinical intervention. Methods Total 96 cases diabetic patients with complete information were chosen in Department of Endocrinology of the 3rd People's Hospital of Bengbu from September 2017 to November 2018, in which there were 60 cases in diabetic foot group (DF) and 36 cases in non-diabetic foot (NDF) group. The data of patients' sex, smoking, glycosylated hemoglobin (HbA1c) levels, diabetes duration and SP level were collected. Multiple factors logistic regression analysis was used to screen out independent predictive factors of DF. Serum SP levels in the two groups were tested and compared. Results Multivariate logistic regression analysis indicated that smoking (OR=8.250, 95% CI:3.201-21.265, P<0.001) and SP levels (OR=9.000, 95% CI:3.466-23.370, P<0.001) were risk factors for DF. The SP level of DF group was (54.47±16.72) pg/mL, and that of NDF group was (116.47±19.00) pg/mL. The serum SP level of DF group was significantly lower than that of NDF group (P<0.05). In the DF group, the serum SP level in severe and moderate patients groups were lower than that in the mild group (all P<0.05).The AUC of SP was 0.994, which had a strong significance for the diagnosis of diabetic foot (P<0.05), and the cut off value was 83.30. Conclusion The smoking and SP level are the risk factors for DF, and SP level is negatively correlated with DF severity.