Objective ·To investigate the clinical, pathological, and molecular genetic features and prognosis of epithelioid hemangioendothelioma (EHE) patients. Methods ·Clinical and follow-up data of 12 EHE patients diagnosed at Renji Hospital, Shanghai Jiao Tong University School of Medicine from September 2016 to December 2023 were collected. Tissue samples were analyzed using hematoxylin-eosin (H-E) staining, immunohistochemistry (IHC), and fluorescence in situ hybridization (FISH). Results ·Among the 12 patients, there were 3 males and 9 females, with a mean age of (47.17±11.15) years. Tumors were located in the liver (6 cases), lung (4 cases), mediastinum (1 case), and supraclavicular region (1 case). Nine patients were asymptomatic, while 3 presented with mild symptoms such as chest tightness and fatigue. CT imaging revealed that EHE patients with involvement of livers and lungs exhibited multiple nodules, and 2 cases had tumors in both organs. Patients with tumors in the supraclavicular region and mediastinum presented with solitary nodules. H-E staining demonstrated that tumor tissues were composed of epithelioid, dendritic, and intermediate cells, arranged in acinar, cord-like, or clustered patterns. Epithelioid cells had round vesicular nuclei and eosinophilic cytoplasm, with some showing a signet-ring appearance and cytoplasmic vacuoles. The stroma contained a mucoid matrix. IHC staining revealed that mesenchymal endothelial markers, including vimentin, CD31, ETS transcription factor ERG, and factor Ⅷ-related antigen, were positive in the tumor tissues, while epithelial markers showed low positivity with weak staining. The Ki-67 indexes were also low. FISH analysis showed that 10 patients had a calmodulin-binding transcription activator 1 (CAMTA1) gene break, while 2 patients had a transcription factor E3 (TFE3) gene break. Of the 12 patients, 11 were followed up for 2 to 38 months, with a mean follow-up time of 21.7 months. Three patients achieved tumor-free survival, 6 were alive with tumors, 1 died 4 months after surgery, and 1 died of heart disease 24 months after surgery. Conclusion ·EHE has atypical clinical features, a tendency to recur, a and variable prognosis. Accurate diagnosis requires a combination of histopathology, IHC, and a molecular testing.