Cytolytic T lymphocyte-associated Ag-4 (CD152) is a negatively regulating molecule, which is primarily expressed on T cells following their activation. In this study, we have examined the role of CTLA-4 expression in experimental blood-stage malaria. Similar to human malaria, CTLA-4 is expressed on CD4+ T cells of C57BL/6 mice after infection with Plasmodium berghei. A kinetic analysis revealed that CTLA-4 expression was increased on day 5 postinfection and reached a peak on day 9 postinfection, when almost 10% of splenic CD4+ T cells expressed CTLA-4. Blockade of CTLA-4 in vivo by a specific mAb and subsequent challenge with P. berghei caused neurological signs reminiscent of murine cerebral malaria and earlier death. Histologic examination of brain sections from anti-CTLA-4-treated mice revealed pathologic changes such as hemorrhages and edema, which were absent in control mice. Furthermore, treatment with anti-CTLA-4 also reversed the extensive loss of CD4+ T cells and the suppressed T cell response occurring during blood-stage malaria. Our data suggest that CTLA-4 expression prevents immune pathology by restricting T cell activation during malaria. They also indicate that the development of cerebral malaria is mediated by a failure to down-regulate T cell activation.