Stress is reportedly known to affect the severity of acute pancreatitis, yet the effect has not been without controversy. We investigated the influence of restraint stress on cerulein-induced pancreatitis, especially in relation to endogenous glucocorticoids. In the present study, restraint stress significantly reduced the increase in serum amylase levels but not pancreas weight induced by cerulein, the effect being totally antagonized by pretreatment with mifepristone, a glucocorticoid receptor antagonist. The changes induced by cerulein were prevented by dexamethasone in a dose-dependent manner. Histologically, restraint stress suppressed the intralobular edema, similar to a low dose of dexamethasone, while the latter at a high dose prevented not only the intralobular but also the interlobular edema. These results suggest that restraint stress exerts a beneficial influence on the cerulein-induced pancreatitis, mainly mediated by endogenous glucocorticoids, and it is assumed that short-term steroid therapy has a potential of clinical application for treatment of pancreatitis.