The immune expulsion of gastrointestinal nematode parasites is usually associated with T helper type 2 (Th2) responses, but the effector mechanisms directly responsible for parasite loss have not been elucidated. The intestinal inflammatory response accompanying infection with gastrointestinal helminths is thought to be a contributory factor leading to the expulsion of the parasite. However, we have shown that the intestinal inflammation, which is controlled by interleukin (IL)-4, is not required for parasite expulsion. OX40-OX40 ligand (L) signals have been shown to be important for the development of Th2 immune responses but are also involved in a number of inflammatory diseases including those of the intestine. Here, we have investigated the effect of OX40 and OX40L fusion protein treatment on the induction of protective Th2 responses and enteropathy following infection with the gastrointestinal nematode Trichinella spiralis. Treatment with an OX40-immunoglobulin (Ig) blocking fusion protein resulted in enhanced expulsion of the parasite and an increase in the accompanying mastocytosis, despite unaltered levels of Th2 cytokines. Furthermore, there was a delay in the villus atrophy and crypt hyperplasia usually associated with this infection. In contrast, levels of Th2 cytokines were greatly up-regulated in mice treated with an OX40L-Ig activating fusion protein, yet the expulsion of the parasite and the enteropathy were unaffected. Therefore, OX40 ligation potentiates the Th2 response without enhancing host protective immune responses, whereas blocking the OX40-OX40L interaction enhances host protection without promoting Th2 cytokine responses during Trichinella spiralis infection.