Background and purpose Patients with severe acute pancreatitis are at risk of complications such as sepsis and organ failure that cause significant morbidity and mortality. In current clinical trial, we aimed to evaluate feasibility of plasmapheresis in treatment of severe acute pancreatitis. Materials and methods In this phase 1 clinical trial, twenty patients with severe acute pancreatitis (Ranson’s score ≥ 7) were enrolled. Patients admitted to intensive care unit and standard pancreatitis treatment including bowel rest and intravenous fluid administration started. Subsequently, all patients underwent plasmapheresis up to three sessions every other day, with 2 units of fresh frozen plasma. Results Of twenty patients, 10 (50%) patients were male. The underlying etiology for pancreatitis was recognized to be cholelithiasis in 17 (85%) patients and hypertriglyceridemia in 3 (15%) patients. Eighteen patients presented with abdominal pain that resolved after plasmapheresis (P<0.0001). Fever was reported in 9 patients, resolved in all patients subsequent to plasmapheresis (P=0.001). Adult respiratory distress syndrome was found in 7 patients. All patients recovered subsequent to plasmapheresis (P=0.004). None of the patients died, or suffered plasmapheresis or catheter related complications. Mean length of hospital stay was 10.625 days, and mean intensive care unit length of stay was 5.75. Conclusion Plasmapheresis is a safe modality in treatment of patients with severe acute pancreatitis. It can be used to improve clinical status and patient outcome, although randomized trials are necessary to establish its efficacy.