Egg Ag-stimulated lymphoid cell culture supernatants from schistosome-infected mice significantly inhibited Ag-specific, MHC-restricted proliferative responses of cloned schistosomal egg Ag-specific CD4+, Th-1-type lymphocytes. The inhibitory molecule in the supernatants was found to be the cytokine IL-10. Maximal IL-10 was produced by cells from mice carrying 8-wk schistosome infections, and none by cells from normal mice. IL-10 exerted its biologic activity on APC, and not directly on the cloned lymphocytes, resulting in the inhibition of Th-1 lymphocyte proliferation, whereas Th-2 responses were not affected. Most significantly, IL-10 also affected Th-1 clone activity in vivo, as measured by the inhibition of schistosomal egg Ag-specific local delayed-type hypersensitivity reactions. IL-10 produced in schistosome-infected individuals may play a role in the generation of APC, such as macrophages in schistosomal egg granulomas, unable to efficiently stimulate, but capable of inducing a state of anergy/unresponsiveness in Th-1 lymphocytes. We believe that this state of Th-1 cell anergy translates into the down-regulation of granulomatous hypersensitivity (immunomodulation) characteristically observed in the evolving schistosomal disease.