We characterized the cytokine response and T-cell requirements of mice infected with the intraerythrocytic parasites Babesia microti and WA1. WA1 infections were fatal, whereas B. microti infections were resolved. We measured production of tumor necrosis factor (TNF)-α, interferon-γ, interleukin (IL)-10, and IL-4 by splenic CD4 , CD8 , and γδ T cells using flow cytometry. WA1 inoculation stimulated TNF-α production, whereas resolving B. microti infections were characterized by increased IL-10 and IL-4. The role of TNF-α in WA1 infections was further investigated by inoculating TNFRp55^−/− mice with a lethal dose of WA1. A survival rate of 90% in the TNFRp55^−/− mice indicated that a disruption in the TNF-α pathway abrogated the pathologic mechanism of WA1. Inoculation of WA1 into CD4^−/− and CD8^−/− mice resulted in survival rates of 60% and 78%, respectively, whereas WA1 infection in γδ^−/− and control mice was fatal. These results suggest that CD8 T cells may contribute to the WA1-associated disease. Babesia-infected CD4^−/− mice experienced a longer duration of parasitemia, indicating that CD4 T cells participate in parasite elimination. These studies demonstrate differences in immune responses during fatal or resolving Babesia infections, and they identify TNF-α as an important mediator of the WA1-associated pathogenesis.