Mesenteric panniculitis (MP), also known as sclerosing mesenteritis, is a rare idiopathic condition characterised by chronic inflammation and fibrosis in the mesentery. While small amounts of chylous ascites due to lymph drainage obstruction are not rare in patients with MP, massive ascites is a rare complication. Moreover, protein-losing enteropathy (PLE), a rare intestinal condition of uncompensated plasma protein loss, can occur in patients with MP. To the best of our knowledge, the present study is the first to report MP with massive chylous pleural effusion and PLE in a 56-year-old male presenting with dyspnoea at Osaka Medical and Pharmaceutical University Hospital (Osaka, Japan) in March 2023. Approximately 5 years prior, the patient noticed systemic oedema, transient abdominal pain and fever and weight loss, and was diagnosed with chylous ascites and PLE by abdominal paracentesis and endoscopic examination of the small intestine. Although initial prednisolone (20 mg/day) administration improved the oedema gradual and uncontrolled fluid buildup was observed. Computed tomography revealed pneumothorax, bilateral massive pleural effusion, and pneumonia. Despite extensive antibiotic therapy [voriconazole (300 mg, twice/day), Ampicillin/Sulbactam (3 g x 4/day), and Vancomycin (1,000 mg x 2/day)], the patient succumbed to respiratory failure 1 month later. Autopsy revealed massive chylous ascites, pleural effusion and the presence of thickened and calcified nodules in the mesentery. Histopathological examination showed diffuse fat necrosis with fibrosclerosis, calcification and lymphocytic infiltration within the mesentery. Therefore, a definitive diagnosis of MP was made. The present case highlighted the importance of considering MP as a differential diagnosis in cases of concurrent chylous ascites, pleural effusion and PLE in patients with abdominal pain, fever and weight loss.