We studied the recurrence of upper gastrointestinal bleeding (UGIB) in a cohort of patients who had an episode of peptic ulcer bleed, and we investigated the effect of maintenance treatment with cimetidine, omeprazole, and ranitidine. We identified 952 patients with a hospitalization for an episode of peptic ulcer bleed by searching the General Practice Research Database in the United Kingdom. The mean follow-up time was 33 months. Less than 10% of the cohort presented with a new episode of UGIB. We calculated incidence rates of recurrent UGIB and estimated the relative risk (RR) of UGIB associated with use of the various acid-suppressing drugs. The greatest protection for recurrent UGIB associated with maintenance acid-suppressing treatment was seen with omeprazole (relative risk 0.2; 95% CI, 0.02-1.0). The corresponding estimates with cimetidine and ranitidine were 0.9 (0.3-2.3) and 0.9 (0.5-1.8). Among nonsteroidal anti-inflammatory drug users, concomitant use of omeprazole afforded protection against a new bleed (RR 0.0; 0.0-1.0), and there was a suggestion of a protective effect with misoprostol, 0.4 (0.01-3.2). The degree of lowered risk of recurrent UGIB in patients on omeprazole maintenance therapy compared with cimetidine or ranitidine therapy is comparable with the protection provided through profound reduction of gastric acidity achieved with proton-pump inhibitors.