Penetration and migration of schistosomulae of Schistosoma mansoni through the skin of mice is associated with reduced inflammatory responses especially after a moderate infection. Previous studies to identify the mechanisms by which schistosomulae of S. mansoni suppress inflammatory responses in human skin showed that the excretory/secretory (ES) products of schistosomulae of s. mansoni contain activities that induce production of the antiinflammatory cytokine IL-1ra from human keratinocytes. In the present study we have characterized the ES products of the schistosomulae of S. mansoni to identify the IL-1ra inducing activity. We demonstrate that this anti-inflammatory activity is associated with a protein of molecular mass 16.8 kDa (Sm 16.8). Depletion studies confirm that Sm 16.8 is the major IL-1ra inducing activity in the ES products. A comparison of the proteins in the ES products of schistosomulae of S. mansoni with those of Trichobilharzia ocellata, a bird schistosome that induces an acute inflammation in human skin, shows that Sm 16.8 is absent in the ES products of T. ocellata. Interestingly, ES products of the schistosomulae of T. ocellata were potent inducers of IL-1 alpha from human keratinocytes, whereas ES products from schistosomulae of s. mansoni induce little or no IL-1 alpha secretion from keratinocytes. Functional studies show that Sm 16.8 suppresses antigen induced lymphoproliferative responses in vitro. Addition of Sm 16.8 to spleen or axillary lymph node cell cultures resulted in a significant reduction in antigen induced IL-2 secretion. These studies show that schistosomulae of S. mansoni elaborate an anti-inflammatory, immunomodulatory factor that may help the parasite to evade host immune responses in the skin. Given the capabilities of Sm 16.8 to induce IL-ira and suppress lymphoproliferation, this protein may also have a potential use as a therapeutic agent for inflammatory skin disorders.