Gastro-duodenal mucosa possesses an array of defensive mechanisms and non-steroidal anti-inflammatory drugs have a deleterious effect on most of them. This results in a mucosa less able to cope with even a reduced acid load. The presence of acid appears to be a conditio sine qua non for non-steroidal anti-inflammatory drug-injury, which is in fact pH-dependent. The acute damage induced by acid non-steroidal anti-inflammatory drugs, like aspirin, can be markedly reduced or even prevented by raising intragastric pH with antacids or antisecretory compounds. Animal studies have clearly shown that not only the degree, but also the duration, of acid inhibition is an important factor for prevention of non-steroidal anti-inflammatory drug-induced mucosal damage. As a consequence, proton pump inhibitors (PPIs) appear to be more effective that H2-receptor antagonists both in preventing and treating gastro-duodenal lesions. While acid suppression seems to be the only effective mechanism for ulcer healing, prevention of non-steroidal anti-inflammatory drug-injury might also rely on the mucosal protective activity of these compounds. Clinical pharmacological studies, performed in healthy volunteers, have shown that--as in laboratory animals--elevation of intragastric pH by means of antacids or antisecretory compounds protects against acute NSAID-induced damage. Unlike H2-blockers, PPIs protect from non-steroidal anti-inflammatory drug-injury not only the duodenum, but also the stomach, where the majority of mucosal lesions are usually located. Although elevation of intragastric pH affects non-steroidal anti-inflammatory drug pharmacokinetics and pharmacodynamics in laboratory animals, a lack of drug-to-drug interaction between PPIs and some of these compounds has been reported in humans. To summarize, clinical and experimental pharmacology support the use of PPIs for the prevention and treatment of non-steroidal anti-inflammatory drug-induced gastro-duodenal damage. Acid suppression could, however, represent only one of the many mechanisms by which these compounds protect gastro-duodenal mucosa. Further studies are, therefore, needed to better elucidate the respective role of the various pharmacological actions in their mucosal protective activity as well as to assess the clinical relevance of each of them.