High-grade, poorly differentiated angiosarcoma is a rare, aggressive malignant neoplasm, comprising 1%-2% of head and neck sarcomas. Diagnosis is often delayed, due to its putatively innocuous clinical appearance combined with the unusual morphology. We report here a case of high-grade angiosarcoma in an elderly patient mimicking clinically and radiologically a benign cyst, and histiocyte-like cells on the morphology. The specimen was fixed in 10% buffered formalin solution and embedded in paraffin using routine procedures. Dewaxed paraffin sections were stained with hematoxylin and eosin. Immunoperoxidase stains were performed on the deparaffinized sections using an avidin-biotin-peroxidase complex. The surgical biopsy revealed histiocytic-like cells characterized by medium to large round nuclei, vesicular chromatin, small nucleoli, abundant eosinophilic cytoplasm, and ill-defined cell borders. These cells are intermixed with chronic inflammatory cells and surrounded by the peripheral cuff of lymphoid cells. Rare multinucleated and multilobulated cells were also identified. No vasoformative structures were identified. On the basis of histomorphology alone, a follicular dendritic sarcoma or other histiocytic sarcoma was considered; however, immunohistochemical stains (CD35, CD23, CD21) were negative in the malignant population, as were the melanoma markers (S100, HMB-45, SOX10, and Melan A) and epithelial markers (EMA, AE1/AE3, CK5/6, CK8/18, and p40); B- and T-cell markers stained only admixed mature lymphocytes. In contrast to these negative results, immunohistochemical studies provided compelling evidence of endothelial differentiation showing positive expression of numerous vascular markers, including CD31, CD34, D2-40, ERG, and factor VIII. A diagnosis of poorly differentiated angiosarcoma was rendered. High-grade, poorly differentiated angiosarcoma has dismal prognosis with high risk of recurrences. Knowledge of its atypical clinical and radiological presentation, as well as awareness of its unusual morphology of histiocyte-like cells can lead to the early diagnosis and prompt treatment.