The evidence that ethanol abuse can lead to pancreatitis is overwhelming, but the mechanism (s) by which ethanol causes pancreatic injury and pancreatitis are not known. Many studies have focused on short-term effects of ethanol administration on exocrine pancreatic function, but the results reported have been variable and no clear picture has emerged. Attempts to induce pancreatitis by long-term ethanol administration have, for the most part, failed. We evaluated the effects of ethanol administration on pancreatic secretion of digestive enzymes. These studies indicate that administration of ethanol results in a transient increase in pancreatic amylase output and plasma cholecystokinin (CCK) levels. This phenomenon is mediated by a trypsin-sensitive CCK-releasing factor that is present within the duodenal lumen. These observations lead us to speculate that repeated CCK-mediated, ethanol-induced stimulation of pancreatic digestive enzyme secretion may play a role in the events that link ethanol abuse to the development of pancreatic injury.