Nicotine, an addictive agent in cigarette smoking, has been implicated in the etiology of pancreatitis and pancreatic carcinoma. Very little experimental data are, however, available regarding the effects of nicotine on the structural and functional changes in the exocrine pancreas. Two groups of rats divided into control and nicotine exposed were used. The animals in the nicotine group were maintained for 28 d with ad libitum water containing 0.77 mM of nicotine. At term, the animals were sacrificed, and pancreas was examined for pathological and functional changes. Nicotine induced cytoplasmic vacuolation and cellular edema in the exocrine pancreas. Plasma levels of glucose and insulin and CCK-8-stimulated amylase release in isolated acini were significantly decreased by nicotine, whereas the total cellular amylase content was significantly increased. Analysis of competitive ligand binding data on membranes from isolated acini showed that the Bmax and Kd values for CCK receptors were not significantly changed by nicotine, p > 0.05. These data indicate that a postreceptor mechanism is involved in the inhibition in stimulus-secretion coupling of enzyme secretion by nicotine. The increase in total cellular amylase content and decreased enzyme secretion by nicotine may be implicated in the induction of pancreatic pathology.