The aim of the present study was to elucidate the pathogenic role of endogenous 5-HT in pancreatitis. Injections of cerulein at hourly intervals caused edematous pancreatitis in mice characterized by hyperenzymemia and histological alterations. While the cerulein-induced hyperenzymemia was attenuated in mice pretreated with p-CPA, a 5-HT depletor, it was exaggerated by the preferential 5-HT_2A agonist (DOI), but not by the preferential 5-HT_2B agonist (BW723C86) or the preferential 5-HT_2C agonist (mCPP). Selective 5-HT_2A antagonists (risperidone, spiperone, ketanserin, AMI-193, and MDL 11,939) dose-dependently attenuated the hyperenzymemia; and their potency order, excepting that of ketanserin which has considerable affinity at the 5-HT_2C receptor as well, paralleled their reported pK_i values at the 5-HT_2A receptor. Selective 5-HT_2B (SB204741) and 5-HT_2C (SB242084) antagonists hardly affected the hyperenzymemia. Although the non-selective 5-HT_2A/_2B/_2C antagonists (metergoline, ritanserin, and methysergide) dose-dependently attenuated the hyperenzymemia, they were relatively less potent compared to their high pK_i values at the 5-HT_2A receptor. In another set of experiments, risperidone, but not SB204741 and SB242084, dose-dependently reversed the cerulein-induced histological alteration of the pancreas (inflammatory cell infiltration). These results suggest that endogenously released 5-HT activates 5-HT_2A receptors to aggravate cerulein-induced pancreatitis. We propose that selective 5-HT_2A antagonists may provide a new therapy for acute pancreatitis.