The clinicopathologic, immunohistochemical, and ultrastructural features of soft tissue angiosarcomas are not well defined. Eighty cases of angiosarcoma that involved the deep subcutis, skeletal muscle, retroperitoneum, mesentery, and mediastinum are reported. The lesions occurred in 50 male and 30 female patients who were 5-97 years of age; the peak incidence was in the seventh decade of life. A variety of associated conditions were documented in 20 of these cases, including a history of other neoplasms (some irradiated), synthetic vessel grafts, heritable conditions, and prior trauma or surgery. The angiosarcomas occurred in the extremities (n = 43 cases), trunk (n = 28), and the head and neck (n = 9) regions, with the thigh and the retroperitoneum being the most common sites. They often were characterized as enlarging, painful masses of several weeks' duration and were occasionally associated with acute hemorrhage, anemia, or a coagulopathy. The tumors measured 1-15 cm in diameter (median 5 cm) and frequently were hemorrhagic and multinodular. There was a wide morphologic spectrum within and between cases, including areas similar to cavernous and capillary hemangioma, Dabska tumor, spindle cell and epithelioid hemangioendothelioma, various spindle cell sarcomas, or carcinoma. Histologically, epithelioid angiosarcoma was the most frequently observed pattern; 70% of cases had epithelioid cells that were arranged in nests, clusters, papillae, and gaping vascular channels. Hemorrhage tended to obscure the diagnosis in several cases and often was associated with papillary endothelial hyperplasia-like areas. All 42 cases studied immunohistochemically stained at least focally for Factor VIII-related antigen, and nearly all stained strongly for vimentin, which accentuated the endothelial cells and vessel lumen formation. CD34 antigen was detected in 74% of cases, BNH9 in 72%, and cytokeratins in 35%. Epithelial membrane antigen, S-100 protein, and HMB45 were not detected. Fifty-five percent of the tumors had intracytoplasmic aggregates of laminin. Immunostains for alpha-smooth muscle actin demonstrated a prominent pericytic component in several tumors (24%). Ki67 immunostains with MIB1 indicated high proliferative activity (≥10%) in 72% of cases. p53 immunoreactivity (>20% nuclear staining) was observed in 20% of cases. Ultrastructural studies performed on poorly differentiated areas of 12 cases showed groups of cells, which were frequently epithelioid, surrounded by basal lamina, and closely associated with pericytes, along with intercellular and intracellular lumina with or without red blood cells. Whorls of abundant intermediate filaments, occasional tonofilamentlike structures, and pinocytotic vesicles also were noted. In contrast to the findings of others, Weibel-Palade bodies were not seen. Follow-up in 49 cases (61%) showed that 53% of patients were dead of disease at a median interval of 11 months, whereas 31% had no evidence of disease at a median interval of 46 months. The remaining patients were either alive with disease (14%) or alive but disease status was unknown (2%). There were local recurrences in 20% of cases and distant metastases in 49%, most frequently to the lungs, followed by the lymph nodes, soft tissues, bone, liver, and other sites. These results indicate that angiosarcoma of soft tissue is a high-grade sarcoma. Older patient age, tumor location in the retroperitoneum, and larger tumor size as well as detection of MIB1 in ≥10% of the tumor cell population were all associated with a poorer prognosis.