Neospora caninum is a coccidian parasite of veterinary importance by causing abortion or stillbirth in cattle among other problems in diverse animal species. We assessed an experimental murine model for its suitability to study the immune response to N. caninum infection. Thus, wild-type (wt) C57BL/6 mice and B-cell (and consequently antibody)-deficient microMT mice were infected with N. caninum tachyzoites and sacrificed at days 10, 24 and 29-44 post infection (dpi). Various organs were collected for parasitological and pathological analysis, spleen and serum for immunological investigations. Splenocytes were in vitro-stimulated with N. caninum (NC)- and T. gondii-antigens for assessing T cell proliferation and cytokine production. While wt mice were resistant to disease, microMT mice died starting from 29 dpi onwards. Histological examination of brain tissue from microMT mice exhibited a high infection intensity with multifocal necrotic cerebral lesions, which were absent in the brains of wt mice. NC antigen-stimulated spleen cells of both wt and microMT mice infected with N. caninum showed a marked proliferative depression at 10 dpi. At 24 dpi, this immunosuppression was still maintained in microMT mice whereas it was restored in wt mice. Stimulated splenocytes of infected microMT mice secreted significantly less IFN-gamma and less IL-10 than corresponding wt splenocytes. For IL-10, this difference increased with time. The susceptibility of microMT mice appeared associated to B-cell deficiency, allowing the persistent spread of the parasite causing immunosuppression and finally resulting in a lethal outcome of infection.