The immunopharmacologic and immunopathologic mechanisms through which hemorrhagic enteritis virus (HEV) induces intestinal lesion formation associated with clinical infection is unknown. These studies were designed to 1) determine differences in age susceptibility to HEV infection and parameters which best indicate severity of virus infection, 2) determine the involvement of specific inflammatory mediators in the formation of intestinal lesions by using anti-inflammatory compounds which directly or indirectly inhibit either the synthesis or the mechanism of action of the mediators, and 3) determine the involvement of immunologically-active cells—basophils, connective tissue mast cells (CTMC), and mucosal mast cells (MMC)—in the formation of HEV-induced lesions. Seven-week-old poults were more susceptible to viral infection when compared to four-week-old poults as judged by HEV antigen presence within the spleen, spleen weight/body weight ratio, heterophil to lymphocyte ratio, and changes in serum lipid and albumin concentration. Of those anti-inflammatory agents used, corticosterone, vitamin E, and indomethacin significantly reduced lesion scores. FPL 55712 and FPL 57231, specific leukotriene receptor blockers, markedly increased lesion scores. Inoculated birds had significantly higher MMC counts than uninoculated birds (120±64 vs. 55±39, respectively). CTMC and basophils were unaffected by viral challenge. In addition to the increase of MMC within the lamina propria of the duodenal villus, there was also a concurrent increase in vascular permeability within the lamina propria which was demonstrated using colloidal carbon and vascular permeability within the lamina propria which was demonstrated using colloidal carbon and ferritin as vascular markers. The results of these studies indicate that vasoactive mediators, such as histamine and the eicosanoids, play a role in lesion formation associated with HEV infection, and that a source of at least some of these compounds appears to be the MMC within the lamina propria of the duodenal villus. Finally, some of the other clinical manifestations of HEV infection, such as decreased serum lipid, protein, and albumin, may be a result of increased vascular permeability which results from vasoactive mediator release and action on the vessels of the lamina propria of the intestinal villus.