BACKGROUND Differentiation between benign and malignant subepithelial lesions (SELs) in the upper gastrointestinal tract (UGT) leads to far-reaching clinical consequences. An accurate diagnosis can be challenging because of the insufficient diagnostic yield of upper endoscopy, endoscopic ultrasound (EUS), and different types of biopsy. OBJECTIVE Our aim was to reveal the efficacy of upper endoscopic and EUS features for the differential diagnosis of hypoechogenic SELs (gastrointestinal stromal tumors [GISTs] and leiomyomas) in the UGT. METHODS The research covers a case series study of 27 hypoechogenic SELs in the UGT between 2012 and 2015 at Vilnius University Hospital Santaros Klinikos. Upper endoscopic and EUS features of SELs were recorded. In order to standardize the diagnostic approach to GISTs and leiomyomas, we assigned scores for seven upper endoscopic and EUS features. RESULTS The mean total scores in the GIST group were significantly higher than those in the leiomyoma group: 3.25 ± 1.71 and 0.53 ± 0.83 (p < 0.0001), respectively. Increment by one score increased the odds ratio for GIST 5.87 times (95% CI 1.63-21.11; p = 0.007). The total score demonstrated very good discriminatory features of GISTs against leiomyomas (area under the receiver operating characteristic curve 0.94 [0.86-1]). The cutoff value of 1.5 total score indicated 83.3% sensitivity and 93.3% specificity in diagnosing GISTs. CONCLUSIONS Upper endoscopy and EUS are useful methods in making a definite diagnosis of SELs. Their diagnostic accuracy for the differential diagnosis of GISTs and leiomyomas is sufficient.