BACKGROUND: The purpose of this retrospective analysis was to determine if a short course of prophylactic proton pump inhibitor (PPI) therapy can prevent stomal ulceration after laparoscopic Roux-en-Y gastric bypass (LRYGBP). METHODS: Four hundred forty-nine consecutive patients who underwent LRYGBP and had a minimum of 6 months follow-up were included. Patients were categorized in two groups: patients with Helicobacter pylori at preoperative endoscopy (HP group) and patients without H. pylori (non-HP group). All patients in the HP group were medically treated prior to surgery. In both groups, almost half of the patients received low-dose proton pump inhibitors (omeprazole 20 mg daily) for 1 month following LRYGBP. RESULTS: The incidence of stomal ulceration in the HP group was not statistically different from the incidence in the non-HP group (7/86, 8.14% vs. 41/363, 11.29%; p = 0.559). When comparing the patients who did receive PPI therapy with the patients who did not receive PPI therapy within the non-HP group, there was no significant reduction in development of stomal ulceration (18/169, 10.65% vs. 23/194, 11.86%; p = 0.743). When comparing the patients who did receive PPI therapy with the patients who did not receive PPI therapy within the HP group, there is a significant reduction in development of stomal ulceration (0/41, 0% vs. 7/45, 15.56%; p = 0.0123). CONCLUSION: Development of stomal ulceration in patients tested positive for H. pylori prior to LRYGBP can be prevented by prophylactic low-dose PPI therapy following surgery.