Primary prevention of gastroduodenal ulcer and its major complication, gastrointestinal bleeding, has been studied mainly in the intensive care environment. Proton pump inhibitors (PPIs), H2-receptor antagonists and sucralfate have proved effective. By extension, PPIs are inappropriately prescribed in a variety of clinical situations. In contrast, they are probably underused in patients chronically treated by nonsteroidal anti-inflammatory drugs. This article reviews the situations in which an increased ulcer risk justifies primary prevention. Validated prophylactic options are also addressed.