Penetration of skin by cercariae of Schistosoma mansoni is associated with a local inflammatory response characterised by leukocyte accumulation and tissue swelling. The significance of the inflammation and its relevance to infection of the host is unknown. In this study, we have investigated the mechanisms of the local inflammatory response induced by injecting extracts of Schistosoma mansoni cercariae into guinea pig skin. Intradermal injection of cercarial homogenate or cercarial transformation fluid induced a dose-dependent increase in local edema formation and accumulation of intravenously injected 111In-labeled eosinophils and neutrophils. The responses were rapid in onset and independent of new protein synthesis. The capacity of extracts to induce edema formation and leukocyte accumulation correlated significantly with their proteolytic activity. In addition, extract-induced inflammation was reduced by co-injection with Trasylol, soybean trypsin inhibitor, PMSF, or heparin. A combination of PMSF and heparin virtually abolished extract-induced inflammation. The known inhibitory effect of Trasylol on kallikrein prompted an investigation into the role of kinins in inducing local edema formation. The bradykinin antagonist HOE 140 substantially reduced extract-induced edema whereas bradykinin itself was weak at inducing leukocyte accumulation. The cyclooxygenase inhibitor ibuprofen, the platelet-activating factor antagonist WEB 2086, and the 5-lipoxygenase inhibitor PF5901 had no effect on edema formation. In contrast, extract-induced eosinophil accumulation was reduced by WEB 2086 and PF5901, suggesting that endogenous PAF and leukotriene B4 were involved in recruiting these cells to inflammatory sites. Thus, cercarial proteases induce a local inflammatory response in guinea pig skin that can be attributed, in part, to known mediators of inflammation. It remains to be established whether the response is protective for the host or whether it is beneficial for the parasite. Further understanding of the underlying mechanisms may provide a target for the pharmacologic control of infection in schistosomiasis.