Despite the increasing incidence in food-borne Echinostoma hortense infection, the underlying immune mechanism along with the clinical manifestations and the expulsion of the worms from the mucosal surfaces are not well understood. To clarify the differences in the immune mechanisms induced by E. hortense in the host, we examined the interleukin (IL)-4, IL-5, IL-12, and interferon-gamma profiles and the kinetics in two genetically different mouse strains, BALB/c and C3H/HeN mice, in vivo as well as in vitro. Both the crude extract and the excretory-secretory protein prepared from E. hortense increased the mRNA and protein expressions of IL-4 and IL-5 in the splenocytes isolated from both strains of infected mice. The E. hortense recovery rate of the C3H/HeN mice was much higher than that of the BALB/c mice. When analyzing the sera from the infected BALB/c and C3H/HeN mice, the IL-5 and immunoglobulin (Ig)G1 levels in the infected BALB/c mice were significantly higher than those from the C3H/HeN mice (p < 0.05). Taken together, these results show that the BLAB/c mice with E. hortense infection are more resistant than are the C3H/HeN mice due to the significantly higher induction of protective Th2 immunity.