Abstract Introduction: Malignant Peritoneal Mesothelioma (MPM) is a rare and aggressive intra-abdominal neoplasm originating from mesothelial cells. Although asbestos exposure is a known risk factor, MPM's molecular pathogenesis differs from its pleural counterpart. Case Presentation: A 75-year-old male, with a past medical history of recently diagnosed mesothelioma, presented to the emergency department for a two-week progression of abdominal distension, early satiety, and dyspnea aggravated by activity. One year prior, he initiated medical evaluation for fluid retention and abdominal distension. A recent omental biopsy confirmed the diagnosis of mesothelioma, prompting the initiation of chemotherapy every three weeks. Despite paracentesis performed monthly, the patient experienced worsening shortness of breath and early satiety post-chemotherapy. Discussion: Malignant Peritoneal Mesothelioma poses a diagnostic challenge due to the absence of specific signs or symptoms. Common manifestations include abdominal distension, pain, early satiety, weight loss, dyspnea, chest pain, and fatigue. Rare symptoms encompass new-onset hernia, fever of unknown origin, night sweats, or incidental findings during physical examinations or laparoscopy. Delays in presentation and diagnosis contribute to the advanced stage at diagnosis, with most cases having already spread throughout the abdominal cavity. Three distinct presentations of MPM include the Dry Painful Type, characterized by abdominal pain with minimal ascites; the Wet Type, presenting with abdominal distension and ascites; and the Mixed Type, combining abdominal pain and distension. Paraneoplastic phenomena, such as fever, thrombocytosis, malignancy-related thrombosis, hypoglycemia, hypoalbuminemia, paraneoplastic hepatopathy, and rarely, Coombs-positive Hemolytic anemia, further complicate the clinical picture. Surgical gross and microscopic descriptions of liver biopsies indicated chronic hepatitis with mild portal inflammation, grade 1, and no fibrosis, stage 0. Notably, the omental biopsy confirmed Malignant Mesothelioma of the epithelioid type. Immunohistochemical stains supported the diagnosis, revealing positivity for CK AE1/AE3, calretinin, WT1, CK7 (focally), and GATA3 (focally), while testing negative for BAP1, CDX2, chromogranin, CK20, hepatocyte antigen, PAX8, PSA, synaptophysin, and TTF1. Due to the rarity of MPM, no standardized treatment protocols exist. Cytoreductive surgery (CRS) and hyperthermic intraoperative peritoneal perfusion with chemotherapy (HIPEC) are recommended for selected patients without extraperitoneal disease spread, possessing a good performance status and potential for complete surgical cytoreduction. Systemic chemotherapy, particularly pemetrexed-based regimens, is advocated for patients ineligible for CRS/HIPEC. Conclusion: MPM's aggressive nature poses diagnostic and therapeutic challenges. The scarcity of standardized guidelines emphasizes the importance of ongoing research to enhance understanding, improve diagnostics, and develop targeted therapies Citation Format: Aliya M Khan, Mehmet Hepgur, Aryama Sharma. Unraveling the complexity of malignant peritoneal mesothelioma: A comprehensive case study of diagnosis, clinical features, and therapeutic challenges in a 75-year-old male [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C069.