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Angiosarcoma (AS) is a rare understudied soft tissue sarcoma exhibiting endothelial cell differentiation. We sought to evaluate AS natural history in the largest patient cohort reported to date and further unravel commonly deregulated molecular events of potential therapeutic utility.Medical records of AS patients (n = 222) treated at our institution from 1993 to 2007 were reviewed. Univariable and multivariable analyses were used to identify independent outcome prognosticators. An AS tissue microarray (n = 68 human specimens) was constructed for immunohistochemical analysis of multiple potential drugable kinase-related molecular markers.Forty-three (19.4%) metastatic AS patients and 179 patients (80.6%) with localized disease were included. Median survival of localized versus metastatic AS was 49 (range, 2–188) versus 10 (range, 1–69) months (P < 0.0001). Patients with localized AS who underwent complete surgical resection (n = 136; 76%) demonstrated significantly better outcome compared with those with unresectable tumors (n = 43; 24%; P < 0.0001). Of several factors identified on univariable analysis as significantly adverse for disease-specific survival, tumor size (>5 cm vs. ≤5 cm, P = 0.01) and epithelioid histologic component (P = 0.008) remained significant on multivariable analysis as independent adverse prognosticators in complete resection patients. Immunohistochemistry identified significant overexpression of vascular endothelial growth factor-A and C as well as p-AKT, p-4EBP1, and eIF4E in human AS.AS harbors a dismal outcome and even patients with disease amenable to complete surgical resection exhibit a 5-year disease-specific survival of only 53%. There is a crucial need for better therapies. Data presented here support further study of the AKT/mTOR pathway as novel molecular targets for AS therapy.