Background and Objectives: To describe the clinical and biological characteristics of patients with hypertriglyceridemia-induced acute pancreatitis (HTG-AP) and to evaluate the effectiveness of therapeutic plasma exchange (TPE) in the management of HTG-AP.Materials and Methods: A cross-sectional study was conducted on 81 HTG-AP patients (30 treated with TPE and 51 treated conventionally). The main outcome was a decrease in serum triglyceride levels (<11.3 mmol/L) within 48 h of hospitalization.Results: The mean age of participants was 45.3 ± 8.7 years, and 82.7% were male. Abdominal pain was the most frequent clinical sign (100%), followed by dyspepsia (87.7%), nausea or vomiting (72.8%), and a bloated stomach (61.7%). The HTG-AP patients treated with TPE had significantly lower calcemia and creatinemia levels but higher triglyceride levels than those who received conservative treatment. They also had more severe diseases than those treated conservatively. All patients in the TPE group were admitted to the ICU, whereas the ICU admission rate in the non-TPE group was 5.9%. The TPE patients were more likely to experience a rapid decrease in triglyceride levels within 48 h of treatment than those treated conventionally (73.3% vs. 49.0%,p= 0.03, respectively). The decrease in triglyceride levels did not depend on the age, gender, or comorbidities of the HTG-AP patients or the severity of disease. However, TPE and early treatment in the first 12 h of disease onset were effective in rapidly reducing serum triglyceride levels (adjusted OR = 3.00,p= 0.04 and aOR = 7.98,p= 0.02, respectively).Conclusions: This report demonstrates the effectiveness of early TPE in reducing triglyceride levels among HTG-AP patients. More randomized clinical trials studies with a large sample size and post-discharge follow-up are needed to confirm the effectiveness of TPE methods in managing HTG-AP.