Purpose: We present a rare case of systemic mastocytosis masquerading as advanced liver disease. An 80-year-old Caucasian man was referred for evaluation of ascites and esophageal varices. His history was notable for frequent watery stools occurring on a daily basis and a thirty pound weight loss over the past year that had remained undiagnosed despite an extensive work-up. In the interim, he had been diagnosed with chronic liver disease of unclear etiology based on the presence of esophageal varices, ascites, and hypersplenism. He reported intermittent abdominal cramping but denied fever, night sweats, rashes, itching, or flushing. On exam, he appeared cachectic and his abdomen was distended with shifting dullness. An abdomen/pelvis CT showed hepatosplenomegaly, ascites, and punctate sclerotic bone lesions. Labs were significant for WBC 5.5 × 10(9)/L with 49% monocytes, hemoglobin 11 g/dL, platelets 93 × 10(9)/L, ALT 111 U/L, AST 67 U/L, alkaline phosphatase 601 U/L, total bilirubin 0.9 mg/dL, and INR of 3.3. Ascitic fluid analysis showed a SAAG of 2.6, total protein of 1.6 g/dL, and 350 cells with 88% monocytes. Gram stain, bacterial culture, and cytology of the ascitic fluid were negative. Liver biopsy revealed nodular regenerative hyperplasia. A bone marrow exam was hypercellular with 20% involvement by systemic mastocytosis. Tryptase immunostaining of the liver biopsy revealed mast cells within the portal areas. Additionally, a serum tryptase was 243 ng/dL (nl < 11.5) which confirmed the diagnosis. Conclusion: Systemic mastocytosis is a rare cause of portal hypertension. Possible mechanisms of portal hypertension in mast cell disease include increased blood flow in the splenic vein, splenic arteriovenous shunting secondary to histamine release, increased intrahepatic resistance secondary to mast cell infiltration, and nodular regenerative hyperplasia. In this case, portal hypertension was likely caused by nodular regenerative hyperplasia and infiltration of portal areas by mast cells. The diagnosis of systemic mastocytosis was considered only after realizing that the diarrhea could not be explained by the degree of portal hypertension and noting the presence of sclerotic bone lesions which prompted a bone marrow biopsy and tryptase measurement. This case highlights the fact that systemic mastocytosis should be considered in the differential of causes of portal hypertension in individuals with evidence of advanced liver disease even when the characteristic cutaneous manifestations of mast cell disease are absent.