Rats were infected with Fasciola hepatica and challenged at regular intervals up to 38 weeks using an ex vivo gut loop, a technique developed in our laboratory. The kinetics of the observed immune responses against F. hepatica in gut tissue and serum were investigated and correlated to protection. Immunohistochemical methods were used to measure the frequency of eosinophils, immunoglobulin (Ig)E-positive cells, and mucosal mast cells in the gut loop, and to determine whether the newly excysted juveniles were coated with IgG antibodies or surrounded by eosinophils, or both. Enzyme-linked immunosorbent assays and a radioimmuno assay were used to measure serum antibody reactive with newly excysted juveniles. Results showed that protection was highly correlated with the frequency of eosinophils and IgE-positive cells in the gut, but was only moderately correlated with the frequency of mucosal mast cells. Newly excysted juveniles taken from rats exhibiting high levels of protection were always coated with IgG antibodies and surrounded by eosinophils. Protection was highly correlated with titers of serum IgG1 antibodies directed against newly excysted juveniles, but was only weakly correlated with titers of serum IgA and IgE antibodies. Because protection was highly correlated with IgG1 in gut tissue and serum, and with eosinophils in gut tissue, we suggest that IgG1 and eosinophils are important in protecting rats against F. hepatica.