BACKGROUND: There is very little information available on the incidence of complications and on the best prevention therapy in high-risk patients taking non-steroidal anti-inflammatory drugs (NSAIDs) and/or aspirin. Randomized-controlled trials in such patients are rare for ethical reasons. We studied the incidence of gastrointestinal complications in high-risk patients taking long-term low-dose aspirin or non-aspirin-NSAIDs combined with omeprazole in a real-life clinical setting. METHODS: This was a multicentre, prospective and observational study including 247 consecutive high-risk patients who had a clinical indication for long-term treatment with either low-dose aspirin or non-aspirin NSAIDs and omeprazole therapy. The occurrence of gastrointestinal complications was measured. RESULTS: In addition to a recent history of peptic ulcer bleeding, all patients had at least 1 other risk factor and 112 (45.3%) had 3 or more risk factors; 78.9% were taking low-dose aspirin and the remainder non-aspirin NSAIDs. Mean follow-up was 14.6 +/- 10.38 months. Three patients taking low-dose aspirin developed upper gastrointestinal bleeding (1.2%; 95% CI 0.3-3.5; 1.0 event/100 patients/year). This was similar to the rate observed in studies involving non-high-risk patients taking low-dose aspirin and higher than that observed in patients not taking low-dose aspirin. Two additional patients developed a lower gastrointestinal bleeding event (0.81% (0.04%-3.12%); 0.67 events/100 patients/year), which was within the range expected in NSAID users. CONCLUSIONS: The use of omeprazole in the high-risk patient taking low-dose aspirin or NSAIDs seems to be a safe therapeutic approach in this population and is associated with a low frequency of upper gastrointestinal complications.