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Background: Direct infiltration of the pancreas by acute myeloid leukemia (AML) with acute pancreatitis (AP) as an initial symptom is extremely rare. Only once in the literature, the leukemia cells in AML have been implicated as the cause of AP. Pancreatitis caused by a rare predisposing factor is often misdiagnosed as idiopathic pancreatitis or pancreatitis of other common causes. Severe AP (SAP) progresses rapidly with a high fatality rate. Therefore, it is important to identify the predisposing factors in the early stage of SAP, evaluate the condition, determine prognosis, formulate treatment plans, and prevent a recurrence. Here, we describe a case of SAP due to AML., Case Summary: A 61-year-old man presented to the hospital with fever and persistent abdominal pain. Blood analysis presented significantly elevated serum amylase and severe thrombocytopenia. Computed tomography examination of the abdomen revealed peripancreatic inflammatory effusion. The patient had no common etiologies and risk factors for AP, but the concurrent severe thrombocytopenia could not be explained by pancreatitis. Finally, the bone marrow aspirate and biopsy inspection revealed the underlying reason for pancreatitis, AML (M2 type based on the French-American-British classifications system)., Conclusion: Direct infiltration of the pancrease by acute leukemia, particularly AML cells, is an infrequent cause of AP. Therefore, although AP is a rare extramedullary infiltration characteristic for AML patients, it should be considered when determining the etiology of AP., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)