BACKGROUND: Hyperlipidemic acute pancreatitis (HLAP) is a severe condition marked by elevated triglyceride levels, resulting in significant morbidity. Current treatment options are limited, highlighting the need for effective therapeutic combinations. METHODS: This study was conducted from January 2020 to December 2023 at the First Affiliated Hospital of Soochow University. A total of 130 patients diagnosed with HLAP were enrolled and randomly assigned to two groups: the control group (65 patients) received low molecular weight heparin (LMWH) and insulin, while the observation group (65 patients) received LMWH, insulin, and plasma exchange (PE). Clinical efficacy, serum triglycerides, amylase levels, inflammatory markers (C-reactive protein, tumor necrosis factor-alpha, interleukin-6), and clinical scores (Balthazar score, APACHE II) were compared between the groups. RESULTS: The observation group demonstrated a significantly higher total effective rate of 90.32% compared to 73.01% in the control group (χ CONCLUSION: The combination of LMWH, insulin, and PE is effective in managing HLAP, significantly alleviating symptoms and reducing inflammatory markers and triglyceride levels. These findings suggest that this treatment regimen could be a valuable addition to clinical practice for HLAP.