Background and Objectives: Gastrointestinal stromal tumors (GISTs) represent the largest group of subepithelial tumors (SET) of the upper gastrointestinal (GI) tract. They may show malignant behavior, in contrast to other SET. Endoscopic ultrasound (EUS) is frequently used to characterize SET. With the introduction of contrast-enhanced ultrasound (CEUS) into EUS (CE-EUS), distinct enhancement patterns can be detected. In the presented study, the characteristic features of CE-EUS in GIST are analyzed and compared with those of other SET. Materials and Methods: Consecutive patients from four centers with SET of the upper and middle GI tract were included and received endoscopic or transcutaneous CEUS. The results were compared with EUS-guided tissue acquisition, forceps biopsy, or surgical resection. Results: Forty-two out of 62 (68%) patients had SET of the stomach, 17/62 (27%) of the small intestine, 2/62 (3%) of the esophagus, and 1/62 (2%) extra intestinal, Eighty-one percent underwent surgery. Leiomyoma was found in 5/62 (8%) and GIST in 57/62 patients (92%). Thirty-nine out of 57 (68%) patients had GIST lesions in the stomach, 17/57 (30%) had GIST of the small intestine, and 1/57 (2%) patients had extraintestinal GISTs. GIST size was 62,6 42.1 (16-200) mm. Hyperenhancement had a sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 98%, 100%, 100%, 93%, and 98% for the diagnosis of GIST, Fifty out of 57 patients with GIST (88%) showed avascular areas in the center of the lesions, Conclusion: CE-EUS and CELTS show hyperenhancement and avascular areas in a high percentage of GIST but not in leiomyoma. Thus, GIST and leiomyoma can be discriminated accurately.