BACKGROUND: Digestive and liver diseases are a source of significant morbidity, mortality, and health-care costs for the U.S. population. An annual report of the toll of these diseases could be helpful to clinicians, policymakers, and researchers. AIM: To describe the epidemiology of gastrointestinal and liver diseases in the United States using data from privately and publicly held databases. METHODS: We collected data from the National Center for Health Statistics, the National Ambulatory Medical Care Survey, the National Inpatient Sample, the Centers for Disease Control and Prevention, and the National Cancer Institute, as well as proprietary pharmaceutical databases to construct a report on the impact of gastrointestinal and liver diseases on the U.S. population. We compiled information on causes of death, hospitalization, clinic visits, cancer incidence, and mortality and infectious disease incidence from these databases, and extracted data specific to gastrointestinal diseases. Because of the high costs associated with medications used to treat gastrointestinal diseases, we also include in this year's report a special section on pharmacoepidemiology and pharmacoeconomics. RESULTS: Colorectal cancer continues to be the leading cause of GI-related death, although the data indicate a downward trend in deaths. Abdominal pain, diarrhea, vomiting, and nausea are the most common GI symptoms precipitating a visit to the physician, and GERD is the most common GI-related diagnosis given in office visits. Chest pain not specified to be cardiac in origin is the most common cause of inpatient admission possibly related to GI disease, with cholelithiasis and pancreatitis following. Americans spend in excess of $10 billion/yr on proton pump inhibitors (PPIs), and two of the top five selling drugs in the United States are PPIs. Trends in PPI use demonstrate turbulent changes, likely reflecting both new drug entries into the field, as well as drug marketing. The number of PPI prescriptions/yr in the United States has doubled since 1999. Twenty-three drugs used for gastrointestinal diseases are among the top 200 generic drugs used in the United States. CONCLUSIONS: Gastrointestinal and liver diseases are significant contributors to the morbidity, mortality, and health-care expenditures of the U.S. population. © 2006 by Am. Coll. of Gastroenterology Published by Blackwell Publishing.