Toxoplasma infection is a major cause of severe foetal pathology both in humans and in domestic animals, particularly sheep. We have previously reported the development of an experimental model to study congenital toxoplasmosis in the rat. Here we demonstrate that, as in humans, total protection against congenital toxoplasmosis can be achieved regardless of the strain of Toxoplasma gondii used to infect rats, or when initial and challenge infections were carried out with different strains. Chronic infection is associated with a highly specific immunity that involves both B-and T-cell responses beginning at day 10 postinfection. The antibody isotype analysis revealed that whereas immunoglobulin (Ig)G2b is the major elicited isotype, no IgG1 antibodies are detected. T cell proliferation was assayed using crude Toxoplasma extracts or excretory-secretory antigens (ESA). The analysis of T cell supernatants showed the specific secretion of both interleukin-2 and interferon-gamma by activated T cells. Immunization of rats before pregnancy with either crude Toxoplasma extracts or with ESA elicited a B cell response that included antibodies of the IgG1 isotype and conferred on the newborns high levels of protection. Preliminary experiments of immunization using two HPLC-purified ESA, GRA2 and GRA5, conferred, a significant protection although to a lesser extent. This experimental model represents an attractive model for the identification of future vaccine candidates against congenital toxoplasmosis.