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Background and aimsAt present, evidence on the association between high-density lipoprotein cholesterol (HDL-C) levels and aggravation of acute pancreatitis (AP) is limited. This study aimed to investigate the relationship between the lowest HDL-C level during intensive care units (ICU) stay and AP aggravation and to determine the optimum cutoff lowest HDL-C level.MethodsPatients admitted to the ICU of the Shandong Provincial Hospital for AP from 2015 to 2021 were included. The lowest HDL-C level during ICU stay was set as the independent variable, and the progression or non-progression to severe AP (SAP) was set as the dependent variable. Univariate and multivariate analyses were performed to determine the relationship between the two variables, and receiver operating characteristic (ROC) curves were plotted to analyze the predictive ability of the lowest HDL-C level for progression to SAP.ResultsThis study included 115 patients. The difference in the lowest HDL-C level between the SAP and moderately SAP groups was significant (P < 0.05). After adjusting for covariates, the lowest HDL-C level showed a negative correlation with the occurrence of SAP, with a relative risk of 0.897 (95% confidence interval: 0.827–0.973). The area under the ROC curve for prediction of AP aggravation by the lowest HDL-C level was 0.707, and the optimum cutoff lowest HDL-C level was 0.545 mmol/L.ConclusionNo less than 0.545 mmol/L of the HDL-C level during ICU stay may be an independent protective factor for the aggravation of AP.