L eukocytes have been implicated in the pathogenesis of ischemic acute renal failure (ARF), but the roles of the individual cell types involved are largely unknown. Recent indirect evidence suggests that T cells may play an important role in a murine model of ARF. In the current study, we found that mice deficient in T cells (nu/nu mice) are both functionally and structurally protected from postischemic renal injury. Reconstitution of nu/nu mice with wild-type T cells restored postischemic injury. We then analyzed the contribution of the individual T cell subsets to postischemic injury and found that mice deficient in CD4⁺ T cells, but not mice deficient in CD8⁺ T cells, were significantly protected from ARF. Direct evidence for a pathophysiologic role of the CD4⁺ T cell was obtained when reconstitution of CD4-deficient mice with wild-type CD4⁺ T cells restored postischemic injury. In addition, adoptive transfers of CD4⁺ T cells lacking either the costimulatory molecule CD28 or the ability to produce IFN-γ were inadequate to restore injury phenotype. These results demonstrate that the CD4⁺ T cell is an important mediator of ischemic ARF, and targeting this cell may yield novel therapies.