Experimental studies suggest that nitric-oxide releasing drugs reduce gastroduodenal damage induced by non-steroidal anti-inflammatory drugs, but it is not known whether these agents have this effect in humans. The aim of the present study was to evaluate the risk of upper gastrointestinal bleeding in patients who receive aspirin and nitrates for vascular occlusive diseases. This was a retrospective case-control study of 736 consecutive patients admitted with upper gastrointestinal bleeding, compared with 1472 age- and sex-matched hospital controls. Chronic low-dose aspirin regimens had been used by 12.6% of cases and 5.7% of controls, nitrates by 4.8% and 5.8%, and combined nitrates and low-dose aspirin by 2.7% and 1.9%, respectively. Logistic regression analysis identified low-dose aspirin use as an independent risk factor for gastrointestinal bleeding, whereas nitrate use was found to be a protective factor. The combination of both nitrate and low-dose aspirin was not associated with an increased risk of bleeding.