Aspirin use is associated with gastroduodenal mucosal damage and increased risk of upper gastrointestinal (GI) bleeding. Many aspirin users should receive prophylactic treatment since they often have several risk factors for upper GI complications. The best therapeutic approach for reducing GI toxicity in low-dose aspirin users is still ill-defined as only a few studies have focused on this problem. Omeprazole appears to be very effective in reducing both acute gastroduodenal mucosal damage and upper GI bleeding in the high-risk patient taking low-dose aspirin, but data with other anti-ulcer agents are lacking (misoprostol) or inconsistent (ranitidine) at present. The role of Helicobacter pylori is controversial in NSAID users, but there is now wide agreement that H. pylori infection increases mucosal damage and the risk of upper GI bleeding in low-dose aspirin users.