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Background: Malignant peritoneal mesothelioma (MPM) is an extremely rare tumor with nonspecific clinical manifestations, which is extremely difficult to diagnose. Herein, we reported a case of MPM in the abdominal cavity with massive short-term ascites as the first symptom., Case Summary: A 65-year-old woman presented to the hospital with abdominal pain, distention, and shortness of breath that persisted for 15 d. The serum CA-125 level was 1075 U/mL. The abdominal computed tomography showed massive ascites and no obvious tumor lesions. The pathological examination of the ascitic fluid showed numerous heterotypic cells with some papillary structures. The immunohistochemistry and fluorescence in situ hybridization showed the deletion of CDX2 (-), WT-1 (-), Ki-67 (about 10% +), CEA (-), Glut-1 (+++), desmin (-), PD-L1 (-), and CDKN2A (P16). The final diagnosis was MPM. The patient refused tumor cytoreductive surgery and received two cycles of cisplatin plus pemetrexed bidirectional chemotherapy. In the second cycle, she received an additional cycle of hyperthermic intraperitoneal chemotherapy and immune checkpoint inhibitor therapy due to massive recalcitrant ascites. She died of disease progression 2 mo after diagnosis., Conclusion: In case of massive unexplained ascites, the possibility of MPM should not be excluded to avoid misdiagnosis and delay in treatment., Competing Interests: Conflict-of-interest statement: The authors declare that the study was conducted without any business or financial relationships that could be interpreted as potential conflicts of interest., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)