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BACKGROUND Although acute pancreatitis associated with hyperparathyroidism has occasionally been reported, acute pancreatitis with metabolic encephalopathy caused by hyperparathyroidism combined with paraneoplastic syndrome is an extremely rare entity and poorly described in the literature. CASE SUMMARY We present a case of a 56-year-old female with upper abdominal discomfort and intermittent nausea and vomiting for 1 wk, without apparent abdominal pain or bloating, no jaundice and decreased blood pressure at the outset. The patient was ultimately diagnosed with moderately severe acute pancreatitis (according to the revised Atlanta classification of acute pancreatitis) combined with metabolic encephalopathy secondary to hypercalcemia caused by primary hyperparathyroidism associated with paraneoplastic syndrome. After active treatment of acute pancreatitis, massive fluid resuscitation, resection of parathyroid and uterine malignant tumors, neoadjuvant chemotherapy and other treatments, her serum calcium eventually returned to the normal level. The patient was successfully discharged from hospital. CONCLUSION This is the first case of acute pancreatitis caused by primary hyperparathyroidism associated with paraneoplastic syndrome.