T cells contribute to the pathophysiology of ischemic stroke by yet unknown mechanisms. Mice with transgenic T-cell receptors (TCRs) and mutations in costimulatory molecules were used to define the minimal immunologic requirements for T cell–mediated ischemic brain damage. Stroke was induced in recombination activating gene 1–deficient (RAG1^−/−) mice devoid of T and B cells, RAG1^−/− mice reconstituted with B cells or T cells, TCR-transgenic mice bearing 1 single CD8⁺ (2C/RAG2, OTI/RAG1 mice) or CD4⁺ (OTII/RAG1, 2D2/RAG1 mice) TCR, mice lacking accessory molecules of TCR stimulation (CD28^−/−, PD1^−/−, B7-H1^−/− mice), or mice deficient in nonclassical T cells (natural killer T [NKT] and γδ T cells) by transient middle cerebral artery occlusion (tMCAO). Stroke outcome was assessed at day 1. RAG1^−/− mice and RAG1^−/− mice reconstituted with B cells developed significantly smaller brain infarctions compared with controls, but thrombus formation after FeCl₃-induced vessel injury was unimpaired. In contrast, TCR-transgenic mice and mice lacking costimulatory TCR signals were fully susceptible to tMCAO similar to mice lacking NKT and γδ T cells. These findings were corroborated by adoptive transfer experiments. Our data demonstrate that T cells critically contribute to cerebral ischemia, but their detrimental effect neither depends on antigen recognition nor TCR costimulation or thrombus formation.