T helper type 2 (Th2) responses have been shown to be important in protective responses to gastrointestinal (GI) helminth infections and in the development of the intestinal pathology accompanying expulsion of the parasite. Different inbred mouse strains have been shown to develop different cytokine profiles following infection with GI helminths with increased resistance observed in those strains where Th2 cytokines predominate. The aim of this study was to determine the role of IL-4, IL-13 and IL-4Rα and the impact of host background on the development of the protective and pathological responses induced by infection with the gastrointestinal helminth Trichinella spiralis. IL-4, IL-13 and IL-4Rα were required for the generation of Th2 responses to T. spiralis; however, the role these responses play in the development of protection and enteropathy was less clear. IL-4Rα-deficiency mice resulted in substantially reduced parasite expulsion, intestinal pathology and Th2 responses. Similarly, lack of IL-13 resulted in inhibited expulsion and the development of enteropathy. Although Th2 responses were reduced in BALB/c IL-4–/– mice, neither expulsion nor enteropathy were different from wild-type mice. In contrast, C57BL/6 IL-4–/– exhibited delayed expulsion and reduced pathology, suggesting that host genetics are important in the function of individual cytokines. Thus, differences in background genotype may be an important component in the development host protection and the development of intestinal pathology accompanying the loss of GI helminths.