BACKGROUND Aspirin-related peptic ulcers are a common disorder. However, whether or not aspirin should be continued during treatment for aspirin-related ulcers remains unclear. OBJECTIVE To compare esomeprazole alone with esomeprazole plus aspirin in the treatment of aspirin-related peptic ulcers and to investigate the independent factors associated with the failure of ulcer healing. METHODS From January 2008 to July 2011, patients with aspirin-related peptic ulcers were randomized to receive esomeprazole (40 mg per day) alone or esomeprazole (40 mg per day) plus aspirin (100 mg per day) for 8 weeks. The subjects with Helicobacter pylori infection were treated with standard triple therapy. Follow-up endoscopy was carried out at the end of the 8th week. The primary end point was the healing of peptic ulcers. RESULTS In all, 178 patients (89 receiving esomeprazole alone and 89 receiving esomeprazole plus aspirin) were enrolled and underwent follow-up endoscopy. The healing rate of ulcers by modified intention-to-treat analysis was 82.5% (95% confidence interval (CI), 74.2-90.8%) among patients treated with esomeprazole alone and 81.5% (95% CI, 73.0-90.0%) among patients treated with esomeprazole plus aspirin (difference, 1.0%; 95% CI, -11.2 to 12.6%). The per-protocol analysis yielded similar results (healing rate: 83.1% vs. 83.8%, respectively; difference, 0.7%; 95% CI, -11.2 to 12.6%). Multivariate analysis disclosed that use of steroids during treatment (odds ratio: 5.6; 95% CI, 1.1-27.7%) was the only independent factor associated with the failure of ulcer healing. CONCLUSIONS The observed ulcer healing rates were comparable in the esomeprazole and esomeprazole-plus-aspirin groups, but the wide CIs do not rule out clinically meaningful differences of more than 10%.