Two strains of Toxoplasma gondii with different capacities to induce disease and brain lesions in mice were used to study the effects of reinfection with the parasite on a previously infected host. In spite of marked antibody and cell-mediated immune responses, chronically infected mice developed disease and died of acute toxoplasmosis when reinfected with a strain different from the one causing the primary infection. Moreover, the marked antibody and cell-mediated immune responses of the chronically infected mice did not prevent invasion of their brains and formation of tissue cysts by the reinfecting strain. Tissue cysts of the reinfecting strain were demonstrated in the brains of the chronically infected and subsequently reinfected mice. These results highlight the importance of strain differences in the pathogenesis of toxoplasmosis.