Chronic alcohol consumption is known to increase the susceptibility to acute and chronic pancreatitis and it is likely that a co-factor is required to initiate the progression to alcoholic pancreatitis. The severity and complications of alcoholic and non-alcoholic acute pancreatitis may be influenced by a number of co-factors including endotoxemia. To explore the effect of a possible co-factor we used endotoxin (LPS) as a tool to induce cellular injury in the alcoholic pancreas. Single, increasing doses of endotoxin were injected into rats fed an alcohol or control diet and killed 24 hours after the injection. We examined the mechanism by which LPS exacerbates pancreatic injury in alcohol-fed rats and whether the injury is associated with apoptosis or necrosis. We show that chronic alcohol exposure alone inhibits apoptosis through the intrinsic pathway and the down-stream apoptosis executor caspase-3 when compared to controls. Pancreatic necrosis and inflammation increased after LPS injection in control and alcohol-fed rats in a dose-dependent fashion but with a significantly greater response in the alcohol-fed animals. Caspase activities and TUNEL positivity were lower in the alcoholic pancreas injected with LPS, while the histopathology and inflammation were more severe compared to control fed animals. Assessment of a putative indicator of necrosis, the ratio of ADP/ATP indicated that alcohol exposure accelerates pancreatic necrosis in response to endotoxin. These findings suggest that the pancreas exposed to alcohol is more sensitive to LPS-induced damage because of increased sensitivity to necrotic cell death, rather than apoptotic cell death. Similar to the liver, the pancreas is capable of responding to LPS with a more severe response in alcohol-fed animals, favoring pancreatic necrosis rather than apoptosis. We speculate that this mechanism may occur in acute alcoholic pancreatitis patients.