In the UK certain anti-ulcer agents are used for prophylaxis against non-steroidal anti-inflammatory drug (NSAID) toxicity. The objective of this study was to compare the incidence of hospitalisations for gastrointestinal events during exposure to these ulcer-healing drugs coprescribed with NSAIDs. METHODS: This was a population based, observational, record linkage study which included Patients all patients (427,786) registered with general practitioners in Tayside, Scotland between 1989 and 1994. Redeemed prescriptions for NSAIDs and anti-ulcer drugs, and hospital discharge diagnoses of patients to whom they were given, were obtained. RESULTS: The risks of hospitalisation for a gastrointestinal event during concurrent exposure to NSAIDs and either misoprostol or proton-pump inhibitors, adjusted for recorded risk factors, were no greater than during exposure to NSAIDs alone in patients with and without a prior history of such events. In contrast, adjusted event rates were twice as high during combined exposure to H2 receptor antagonist and NSAID compared with NSAIDs alone in patients with a prior history (p<0.001), and 20% higher in patients without (p<0.001). Risks of hospitalisations for gastroduodenal ulcers, erosions, gastritis and duodenitis during exposure to misoprostol were 23% less than those during exposure to H2 receptor antagonists (p<0.001). No such difference was found with proton pump inhibitors. Despite the apparent greater efficacy of misoprostol and proton pump inhibitors relative to H2 receptor antagonists in patients with a prior history, their use was less common in these high risk patients. CONCLUSIONS: The observed preferential use of H2 receptor antagonist co-therapy in patients at a high risk of NSAID associated gastrointestinal complications appears not to be justified. Despite substantial confounding between the use of ulcer-healing drugs and recorded risk factors, in the setting of primary care, misoprostol and to a lesser extent proton-pump inhibitors appeared to be effective in reducing hospitalisation for gastrointestinal events associated with NSAID use.