Objective To explore the relationship between secretory leukocyte protease inhibitor (SLPI) and acute coronary syndrome (ACS). Methods A total of 243 patients with ACS and 242 age- and gender- matched individuals with normal coronary arteries undergoing coronary angiography from July 2018 to September 2020 in Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine were enrolled. The serum SLPI level was detected by enzyme-linked immunosorbent assay, and the correlation between serum SLPI level and ACS was evaluated. Immunofluorescence was used to detect the localization of SLPI in ventricular aneurysm. Results The serum SLPI level in ACS patients was significantly higher than that in healthy controls [(452.0±167.6) ng/L vs. (420.5±154.3) ng/L, P=0.032]. Multivariate Logistic regression analysis showed that the increased serum SLPI level was an independent risk factor for ACS [odds ratio(OR)=1.309, 95% confidence interval (CI):(1.040-1.648), P=0.022]. Immunofluorescence showed SLPI was co-expressed with alpha-smooth muscle actin (α-SMA) in the ventricular aneurysm. Conclusions Serum SLPI level is an independent risk factor for ACS, and SLPI is expressed in smooth muscle cell of ventricular aneurysm.