In common with many intestinal nematode infections, Trichinella spiralis infections in mice are associated with a pronounced intestinal mast cell hyperplasia. The expulsion of the parasite from the gut is temporally associated with intestinal mastocytosis and mast cell function reflected by the secretion of mast cell protease into tissue and serum. In vivo, mucosal mast cell production is highly dependent upon T cell-derived cytokines including IL-3 and IL-4. We present data here to show that intestinal mast cell hyperplasia induced by helminth infection is also dependent upon the production of stem cell factor (SCF). Neutralization of SCF by anti-SCF or anti-SCF receptor mAb completely abrogated the mast cell hyperplasia generated by T. spiralis infection. Moreover, worm expulsion was dramatically delayed in treated mice and a reduced intestinal eosinophilia was observed. These effects did not appear to be mediated through alteration of Th cell responses and the parasite-specific serum antibody response was not affected. The reduction in the mast cell response and worm expulsion observed after SCF neutralization were reversible following cessation of monoclonal treatment. The data presented here clearly demonstrate a major role for SCF in the generation of intestinal mastocytosis and the host protective immune response following parasitic infection.