Sclerosed hemangiomas of the liver are rare. To date, their histopathology, immunohistochemistry, and the role of mast cells (MC) in their histogenesis have not been systematically studied. Clinical, histopathologic and immunohistochemical features of 20 sclerosed hemangiomas were compared with those of 18 sclerosing cavernous hemangiomas. The number of MC was quantified and compared in all cases, using a tryptase immunostain. Compared to patients with sclerosed hemangiomas, those with sclerosing hemangiomas were younger (mean age, 63 versus 71 years); had larger tumors (mean 6 +/- 4.73 versus 3 +/- 2.2 cm); presented with a mass more frequently, and epigastric pain less frequently. Sclerosing hemangiomas, but not sclerosed hemangiomas, were more frequent in males than in females. Sclerosing hemangiomas occurred much more frequently in the right lobe than sclerosed hemangiomas. Sclerosing hemangiomas had less fibrosis, hyalinization, and elastic fibers than sclerosed hemangiomas (p = 0.00004). Numerous thick-walled blood vessels were a feature of sclerosed hemangiomas but not of sclerosing hemangiomas. Collagen IV, and laminin were more uniformly positive in sclerosing hemangiomas than in sclerosed hemangiomas. Increased immunoreactivity for smooth muscle actin was present in sclerosed hemangiomas more often than in sclerosing hemangiomas. FVIII-R Ag, CD34, and CD31 were more diffusely positive in sclerosing hemangiomas than in sclerosed hemangiomas. In sclerosing hemangiomas, the mean number of tryptase-positive MC per high power field (MC/HPF) varied from 8.25 +/- 6.23 in vascular areas to 1.6 +/- 4.01 in sclerotic areas. In comparison, the mean number of MC in sclerosed hemangiomas, was 4.3 +/- 5.01 in vascular areas, and 0.86 +/- 0.58 in sclerotic areas (p = 0.0095). The number of MC was significantly correlated with vascular proliferation and inversely related to the degree of fibrosis (p < 0.0001). This study demonstrates certain distinct clinical and histopathologic differences between sclerosing cavernous hemangiomas and sclerosed hemangiomas of the liver. We have established the presence of MC in those tumors, and suggest possible involvement of the MC in angiogenesis, and the regression process and development of fibrosis.