Aspirin is commonly used in primary and secondary prevention of cardiovascular events. However, its long-term use leads to gastrointestinal compromise, such as gastric mucosal erosions, peptic ulcer, and GI bleeding. These complications are common in our daily clinical practice, as illustrated in the case of a 67-year-old male who has ischaemic heart disease and was on long-term aspirin without any gastric protection for 9 years. He was subsequently admitted for bleeding from gastric ulcers and diagnosed to be positive for H. pylori infection. The risk factors for GI damage and bleeding, and the evidence for gastric protection in long-term aspirin users are reviewed here. High-risk patients, such as those with a history of ulcer disease or gastrointestinal bleeding, should undergo screening and treatment of H. pylori infection. Concomitant use of proton-pump inhibitors is recommended as they are superior to histamine-2 receptor antagonists in prevention of GI bleeding. PPI use should also be encouraged if patients have two or more of the following risk factors: over 60 years old, corticosteroid use, dyspepsia, or gastroesophageal reflux disease symptoms. Further research is needed to determine if H. pylori screening is required prior to commencement of long-term aspirin in the general population.