Concentrations of plasma immunoreactive anionic and cationic trypsin(ogen) were monitored in unanesthetized dogs to investigate diurnal variation, response to food intake, and effects of cholecystokinin octapeptide (CCK-8) plus secretin administration. Identical meals were consumed at the beginning and end of a 24-h period. Plasma levels of both trypsin(ogen)s increased significantly within 30 min of feeding. Second-meal responses were much larger than those following the first meal. Plasma cationic trypsin(ogen) was also elevated during the normal feeding period when food was withheld and dogs in adjacent cages were fed. Small, irregular variations in plasma trypsin(ogen)s occurred during the interdigestive period when blood was sampled every 2 h. CCK-8 plus secretin, in doses shown previously to stimulate exocrine secretion of enzymes submaximally, increased plasma levels of both trypsin(ogen)s dose dependently. Most (greater than 80%) of the immunoreactive cationic trypsin(ogen) in plasma before and after feeding and following CCK-8 was in proenzyme form. We conclude that plasma levels of pancreatic trypsinogens are increased by food intake and low doses of CCK-8. Furthermore, cephalic mechanisms appear to play an important role in mediating the response to food intake.