Adverse effects of non-steroidal anti-inflammatory drugs and antiaggregants on the gastrointestinal tract can be prevented or reduced by rational prescribing, use of proton pump inhibitors and Helicobacter pylori eradication. Non-steroidal anti-inflammatory drugs should not be used to treat patients at high risk for serious adverse effects on either upper gastrointestinal or cardiovascular system. Proton pump inhibitors at standard oral doses are used for the treatment of dyspepsia or gastric and duodenal erosions and ulcers caused by non-steroidal antiinflammatory drug or antiaggregant use. Peptic ulcer hemorrhage is treated with endoscopic hemostasis and proton pump inhibitors (72-hour continuous infusion followed by 4–8 week standard-dose oral treatment). Patients can be stratified into three groups based on the risk for upper gastrointestinal system adverse effects associated with non-steroidal antiinflammatory drugs or antiaggregant use. The absence of risk factors denotes low-risk patient population, one or two risk factors are associated with medium risk; high-risk patients harbor either three or more risk factors or a history of complicated peptic ulcer disease. Helicobacter pylori should be eradicated (if present) in all medium and high-risk patients prior to the introduction of no-nsteroidal anti-inflammatory drugs or antiaggregants, and proton pump inhibitors at standard daily dose should be prescribed for the duration of the treatment. Risk of gastrointestinal hemorrhage should be considered when planning invasive cardiovascular procedures or introducing antiaggregant or anticoagulant treatment. In the context of acute gastrointestinal hemorrhage, antiaggregants should not be discontinued for longer than 7 days and oral anticoagulant therapy should be stopped and replaced with low-molecularweight heparin after complete hemostasis.