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The role of laparoscopy-assisted resection for treating gastrointestinal stromal tumors >5 cm is still disputed. We aimed to assess the advantages of laparoscopy-assisted resection for treating gastrointestinal stromal tumors >5 cm. In total, 1,802 patients with primary gastrointestinal stromal tumors who underwent laparoscopy-assisted surgery or open surgery were retrospectively evaluated. Propensity score matching was performed to reduce confounders. In total, 518 patients with tumor size >5 cm were enrolled in this study (males: 292, 56.4%; females: 226, 43.6%; median age: 58 years, range: 23–85 years). One hundred and twenty-three (23.7%) patients underwent laparoscopy-assisted resection, and 395 (76.3%) patients underwent open resection. After propensity score matching, 190 patients were included (95 in each group). The laparoscopy-assisted surgery group was superior to the open surgery group considering the blood loss (>200 mL: 6.3% vs 22.1%, P =.005), length of midline incision (6.0 ± 0.9 cm vs 9.6 ± 2.1 cm, P <.001), time to first flatus (49.7 ± 10.5 hours vs 63.9 ± 7.4 hours, P <.001), and shorter hospital stay (10.3 ± 3.2 days vs 11.9 ± 2.9 days, P <.001). The difference in relapse-free survival or overall survival between the laparoscopy-assisted surgery and open surgery groups after matching was not significant (all P >.05). On subgroup analysis, the relapse-free survival and overall survival of the laparoscopy-assisted surgery group were comparable to those of the open surgery group, irrespective of tumor location (gastric or nongastric locations) (all P >.05). When performed by experienced surgeons, laparoscopy-assisted resection is feasible and safe for gastrointestinal stromal tumors >5 cm, which showed improved short-term outcomes and comparable oncological outcomes, regardless of whether the tumor had a gastric or nongastric location. [ABSTRACT FROM AUTHOR]