At least two thirds of cirrhotic patients develop esophageal varices during their lifetime. Severe upper gastrointestinal (UGI) bleeding as a complication of portal hypertension develops in about 30%-40% of cirrhotics. Despite significant improvements in the early diagnosis and treatment of esophagogastric variceal hemorrhage, the mortality rate of first variceal hemorrhage remains high (20%-35%). Primary prophylaxis, the focus of this article, is treatment of patients who never had previous variceal bleeding to prevent the first variceal hemorrhage. The potential of preventing first variceal hemorrhage offers the promise of reducing mortality, morbidity, and associated health care costs. This article (1) reviews endoscopic grading of size and stigmata for esophageal and gastric varices, (2) describes data on prevalence and incidence of esophageal and gastric varices from prospective studies, (3) discusses independent risk factors from multivariate analyses of prospective studies for development of first esophageal or gastric variceal hemorrhage and possible stratification of patients based on these risk factors, (4) comments on the potential cost effectiveness of screening all newly diagnosed cirrhotic patients and treating high-risk patients with medical or endoscopic therapies, and (5) recommends further studies of endoscopic screening, stratification, and outcomes in prospective studies of endoscopic therapy. The author's recommendations are to perform endoscopic screening for the following subgroups of cirrhotics: all newly diagnosed cirrhotic patients and all other cirrhotics who are medically stable, willing to be treated prophylactically, and would benefit from medical or endoscopic therapies. Exclude patients who are unlikely to benefit from prophylactic therapies designed to prevent the first variceal hemorrhage, those with short life expectancy, and those with previous UGI hemorrhage (they should have already undergone endoscopy). For low or very low risk cirrhotic patients-those found to have no varices or small varices without stigmata-repeat endoscopy is recommended because screening for progression may be warranted in 2 or more years.