Key Clinical MessageIn low‐ and middle‐income countries, protein‐losing enteropathy is a diagnosis of exclusion. SLE should be on the list of differential diagnoses of protein‐losing enteropathy, especially if the patient had a long history of GI symptoms and ascites.AbstractProtein‐losing enteropathy can rarely be the initial presentation of systemic lupus erythematosus (SLE). Protein‐losing enteropathy is a diagnosis of exclusion in low‐ and middle‐income countries. Protein‐losing enteropathy in SLE should be in the list of differential diagnosis of unexplained ascites, especially if patient had long history of gastrointestinal symptoms. We present a case of 33 years old male with long standing gastrointestinal symptoms and diarrhea attributed previously to irritable bowel syndrome. Presented with progressive abdominal distension, and diagnosed with ascites. Workup for him showed leucopenia, thrombocytopenia, hypoalbumenemia, elevated inflammatory markers (ESR 30, CRP 6.6), high cholesterol level (306 mg/dL), normal renal profile and normal urine analysis. Ascitic tab pale yellow with SAAG 0.9 and positive for adenosine deaminase (66 u/L) sugesstive for tuberculous peritonitis although quantitative PCR and geneXpert for MBT was negative. Antituberculous treatment was started and his condition deteriorated, immediately antituberculous was withdrawal. Further tests revealed positive serology for ANA (1:320 speckled pattern) with positive anti‐RNP/Sm, positive anti‐Sm antibodies. Complements level were normal. He started immunosuppressive therapy (prednisolone 10 mg/day, hydroxychloroquine 400 mg/day, azathioprine 100 mg/day). In addition, his condition is improved Diagnosis was made as SLE with Protein‐losing enteropathy based on hypoalbumenemia (with exclusion of renal loss of protein), ascites, hypercholesrtolemia and exclusions of other mimics as explained later. As well as positive response to immunosuppressive medications. Our patient diagnosed clinically as SLE with protein‐losing enteropathy. Protein‐losing enteropathy in SLE is challenging in diagnosis because of its rarity as well as limitations in its diagnostic tests.