Mechanisms for the spontaneous worm expulsion from the host intestine are not well understood in gastrointestinal trematode models. We studied the role of CD4+ T-helper cells in mediating goblet cell hyperplasia and expulsion of Gymnophalloides seoi from the intestines of C57BL/6 (resistant) and ICR (susceptible) mice. C57BL/6 mice expelled all G. seoi worms within 4 days post-infection (PI), while ICR mice did not completely expel worms until day 7 PI. This difference in worm expulsion was associated with high numbers of mucosal goblet cells in C57BL/6 mice along with alteration of the mucin quality, with changes in the terminal sugar chain and high levels of IL-4 and IL-5 mRNA expression in mesenteric lymph nodes. Adoptive transfer of mucosal CD4+ T-helper cells to syngeneic mice elicited strong goblet cell hyperplasia and a notably accelerated worm expulsion. However, this T-helper cell transfer had no relationship with the alteration of mucin quality. The results showed that CD4+ T-helper cells play an important role as a mediator of goblet cell hyperplasia, but not for functional activation of goblet cells. It is suggested that both T-cell dependent and independent mechanisms operate for expulsion of G. seoi from the mouse intestine.