Background: Long-term prophylaxis with ranitidine reduces the risk of recurrent bleeding in patients with a history of bleeding peptic ulcers. To date, no randomized study has been performed to compare cure of Helicobacter pylori infection versus H2 blocker prophylaxis in patients with bleeding peptic ulcer. Methods: In a prospective randomized study, 95 consecutive patients with H. pylori–associated peptic ulcer bleeding were randomized to either ranitidine prophylaxis (150 mg at night) for 2 years or to H. pylori-eradication with omeprazole 60 mg twice daily plus amoxicillin 750 mg three times daily for 10 days. Results: (Intention-to-treat analysis). Forty-eight patients were enrolled in the ranitidine group; 47 in the omeprazole-plus-amoxicillin group. Mean follow-up was 576 days (77 to 730). Ulcer recurrence rate was 31.3% in the ranitidine group (group 1) versus 6.37% in the eradication group (group 2; p = 0.0018). More patients had recurrent bleeding in group 1 (8.3%) than in group 2 (4.2%) but we were not able to show a statistically significant difference with respect to recurrent bleeding between groups (p = 0.29). Definite cure of H. pylori infection was achieved in 89.3%. Conclusions: Cure of H. pylori infection reduces recurrence of peptic ulcer and therefore rebleeding more effectively than does long-term maintenance therapy with an H2 blocker. (Gastrointest Endosc 1997;46:299-304.)