The role of type I hypersensitivity in the rapid rejection of Trichinella spiralis from actively, and passively immunized rats was examined. Net intestinal fluid secretion, which occurs during the rejection of the parasites, was used to verify the expression of local anaphylaxis and was examined for its possible role in the rejection process. Worm establishment in the small intestine 30 min after intraduodenal inoculation was significantly reduced in rats that were passively immunized with immune serum containing anti- Trichinella IgE as compared with recipients of normal serum. Worm-induced fluid secretion in immune rats was completely inhibited by the combined action of indomethacin and diphenhydramine. However, worm rejection was not affected. L-651,392, a 5-lipoxygenase inhibitor, also failed to prevent rejection. Ketanserin (a serotonin S2 receptor antagonist) and MDL-72222 (a serotonin S3 receptor antagonist) together blunted the rapid rejection response and reduced fluid secretion. Furthermore, intra-arterial perfusion of serotonin into nonimmune rats caused fluid secretion and reduced worm establishment. In nonimmune rats prostaglandin E2, cholera toxin, and hypertonic Krebs-mannitol solution were used to evoke the same level of intestinal fluid secretion as that induced by reinfection in immune rats or by serotonin in nonimmune hosts. When larvae were inoculated into the secreting gut, their infectivity was unaffected. The results suggest that anaphylaxis is involved in the rapid rejection of T. spiralis in immune rats and that serotonin is a possible chemical mediator of worm rejection. Although the mode of action of serotonin in the rejection process remains unknown, its possible involvement through fluid secretion can be ruled out.