Incisional hernias represent a far more common complication after midline incisions than previously estimated. Patients with upper gastrointestinal tract malignancies represent a group of patients at increased risk for incisional hernia formation after undergoing major surgery. Our prospectively designed study included 50 patients who underwent onlay synthetic mesh augmentation of their midline closure along with closure using the small bites technique. At a 12-month follow-up, no incisional hernias were documented. A significant decrease compared to historical controls was achieved, with few minor complications. Mesh augmentation of midline closure in patients with upper gastrointestinal tract malignancies can significantly reduce subsequent incisional hernia formation.