Much of the secondary tissue damage associated with ischaemic stroke is caused by inflammation, but the factors involved in this neuroinflammation remain unclear. This study showed that interleukin-21 (IL-21) expression is greatly increased in the brain of mice following cerebral ischaemic reperfusion injury, that Il21−/− mice have reduced brain injury, and that IL-21 blockade in wild-type mice greatly reduced infarct size. Infiltrating CD4+ T cells were found to be the main source of IL-21 in the post-ischaemic brain in mice. Furthermore, CD4+IL-21+ T cells were shown to surround acute stroke lesions in human post-mortem tissue, which suggests that IL-21 may have a role in tissue injury following stroke in humans.