Background Low-dose aspirin is widely used in the prevention of cardiovascular diseases. However, the use of aspirin is associated with an increased risk of gastrointestinal injury. Methods Low-dose aspirin users with a history of peptic ulcers who did not have gastroduodenal mucosal breaks at initial endoscopy were randomly assigned to receive famotidine (20 mg bid) or omeprazole (20 mg qd) for 6 months. Follow-up endoscopy was carried out at the end of the 6th month and whenever epigastric discomfort, hematemesis or melena occurred. The primary end point was the occurrence of gastroduodenal mucosal breaks. The secondary end points were (1) the occurrence of gastroduodenal ulcers, and (2) the occurrence of gastroduodenal bleeding. Result Between November 2013 and June 2018, 170 patients were randomly assigned to receive either famotidine (n = 84) or omeprazole (n = 86). The incidence of gastroduodenal mucosal breaks was 33.8% among the patients receiving famotidine, and 19.8% among those receiving omeprazole (95% confidence interval [CI]: 0.4% - 27.5%; p = 0.045). The two patient groups had comparable incidence rates of gastroduodenal ulcers (20.0% vs 9.8%; p = 0.071), and gastroduodenal bleeding (2.5% vs 0%; p = 0.243). Multivariate analysis showed that use of the proton pump inhibitor was an independent protective factor (Odds ratio: 0.47; 95% CI: 0.23 - 0.99; p = 0.047), and that smoking was a risk factor for mucosal breaks (Odds ratio: 3.84; 95% CI: 1.52 - 9.71; p = 0.004). Conclusion Proton pump inhibitor was superior to histamine-2 receptor antagonist in the prevention of gastroduodenal mucosal breaks in high-risk users of low-dose aspirin, and smoking was an independent risk factor for developing gastroduodenal mucosal breaks.