BACKGROUND: Serum high-density lipoprotein cholesterol (HDL-c) may influence cancer development. However, its relationship with the histological grade of pancreatic ductal adenocarcinoma (PDAC) is not well understood. This study aims to explore the potential associations between serum HDL-c levels and different histological grades of PDAC. METHODS: This retrospective study included 181 patients with pathologically confirmed PDAC who underwent radical surgery. Clinical data, blood biochemical results, imaging features, and pathological details of the patients were collected, such as age, gender, diabetes, hypertension, tumor grade, tumor size and location, high-density lipoprotein (HDL-c), low-density lipoprotein (LDL), total cholesterol (TC), triglycerides (TG), carbohydrate antigen 19-9 (CA19-9), and carcinoembryonic antigen (CEA). RESULTS: Patients with high-grade PDAC had significantly lower HDL-c levels compared to those with low-grade PDAC across both training and validation cohorts ( CONCLUSIONS: Lower HDL-c levels are associated with high-grade PDAC and lymph node metastasis, suggesting that HDL-c may play a protective role in the progression of PDAC.