ABSTRACT Introduction: The incidence of pancreatitis has increased in recent decades and alcohol was recognized as one of the major causes of pancreatitis as well as gall stones. Nicotine is a major toxin in tobacco and cigarettes and may influence the development of pancreatitis. Caffeine is a natural stimulant widely consumed psychoactive drug. Aim: This study was done to evaluate the influence of nicotine and caffeine on the pathogenesis of alcohol-induced pancreatitis. Materials and Methods: Forty adult male Wister albino rats were divided into four equal groups; control group, alcoholic pancreatitis group, alcoholic pancreatitis with nicotine group and alcoholic pancreatitis with caffeine group. At the end of the experimental period, blood samples were collected for serological study (serum amylase, lipase and blood sugar) and pancreata were processed for light microscopic examination. Results: Histological examination of the pancreas in alcoholic pancreatitis group showed marked pancreatic distortion with marked cytoplasmic vaculations and small deeply stained nuclei of acinar cells. In between the acini there were inflammatory cell infiltration and congested blood vessels. Immunohistochemically, NF-κB and Caspase-3 were increased, while insulin was decreased. These histological/immunohitochemical changes were increased in alcoholic pancreatitis with nicotine group and decreased in alcoholic pancreatitis with caffeine group. Blood glucose, serum amylase and lipase levels were also increased in alcohol pancreatitis group compared to controls. The increase in these enzymes was elevated by alcohol pancreatitis with nicotine group and decreased by alcohol pancreatitis with caffeine group. Conclusion: Nicotine exaggerates the adverse effects of alcoholic pancreatitis while caffeine improves these changes.