Protective response against Babesia microti was studied in Isospora felis-infected mice. Isospora felis-infected mice which were exposed to B. microti on the 28th day post-infection showed absolute resistance against Babesia microti. Interestingly, these mice showed no anti-B. microti antibodies. Mice that received spleen cells from I. felis-infected donors that were subsequently exposed to B. microti showed lower peak parasitemia (10.3% +/- 2.6) compared to those mice that received normal spleen cells (60.9% +/- 15.0), and no spleen cells at all (47.3% +/- 8.5). Treatment of I. felis-infected mice with monoclonal antibodies against L3T4+ cells resulted to a depression of their resistance to B. microti, as clearly manifested by high levels of parasitemia. Findings of the present study demonstrate the role of cell mediated immunity, specifically by L3T4+ T-cells induced by I. felis infection, in providing mice protection against B. microti.