The relationship between intestinal pathology and immune expulsion of gastrointestinal nematodes remains controversial. Parasite expulsion is associated with intestinal pathology in several model systems and both of these phenomena are T cell dependent. Immune expulsion of gastrointestinal helminth parasites is usually associated with Th2 responses, but the effector mechanisms directly responsible for parasite loss have not been elucidated. In contrast, the intestinal pathology observed in many other disease models closely resembles that seen in helminth infections, but has been attributed to Th1 cytokines. We have used infection with the nematode Trichinella spiralis in mice defective for cytokines or their receptors to investigate cytokine regulation of both immunopathology and parasite rejection. Consistent with previous findings, we found that parasite expulsion is IL-4 dependent. Contrary to expectations, however, the enteropathy is not regulated by IFN-gamma but by IL-4. Moreover, abrogation of severe pathology in TNF receptor-defective animals does not prevent parasite expulsion. TNF is therefore involved in intestinal pathology in nematode infections, apparently under regulation by IL-4- and Th2-mediated responses. This work therefore not only reveals a novel interplay between IL-4 and TNF, but also that the IL-4-dependent protective response against the parasite operates by a mechanism other than merely the gross degradation of the parasite's environment brought about by the immune enteropathy.