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Background: The diagnostic efficacy of current tissue sampling techniques for upper GI subepithelial tumors (SETs) appears to be limited. Better tissue acquisition techniques are needed to improve the diagnostic yield in this setting. Objective: Our purpose was to determine the safety and diagnostic yield of EUS-guided needle-knife incision and forceps biopsy (SINK biopsy) of upper GI SETs. Design: Retrospective database review. Setting: Academic tertiary-care referral center. Patients: This study involved 14 consecutive patients referred for EUS evaluation of upper GI SETs with previous unsuccessful attempts at tissue diagnosis by conventional forceps biopsy. Intervention: EUS-guided needle-knife incision and forceps biopsy. Main Outcome Measurements: The safety and diagnostic yield of this method, compared with EUS-guided fine-needle aspiration (EUS-FNA), when possible. Results: SINK biopsy provided tissue samples that were sufficient for definite histologic diagnosis in 13 of 14 cases (diagnostic yield 92.8%). There were 8 gastric GI stromal tumors. In 7 of 8, the size of SINK specimens allowed immunohistochemical analysis, and the evaluation of malignant potential was carried out by means of mitotic index determination in 5 cases (71.42%). SINK biopsies determined the pathological diagnosis of all (4 of 4) nonmesenchymal lesions. Eight patients underwent both EUS-FNA and SINK, with final histologic diagnosis determined in 6 of 8 cases (75%) by SINK versus 1 of 8 cases (12.5%) by EUS-FNA (Fisher exact test, P = .023). There were no procedure-related complications. Limitations: A single-center, retrospective analysis with small sample size. Conclusion: SINK biopsy appears to be an easy, safe, and effective technique for determining the definitive pathological diagnosis, evaluation of the malignant potential, and planning management of SETs. It could be a reliable alternative to conventional FNA, providing larger samples that improve the histologic yield. [ABSTRACT FROM AUTHOR]