Although CD95L is required for T cell receptor (TCR)-induced cell death (TCR-ICD) in T helper 1 cells, the molecular mechanisms mediating TCR-ICD in Th2 cells are unknown. We found that death receptors were not involved in TCR-ICD of Th2 cells because blocking their cognate ligands had no effect on apoptosis of activated Th2 cells. Furthermore, we showed that caspases were not actively involved in TCR-ICD of Th2 cells. However, inhibition of granzyme B (GrB) activity abolished TCR-ICD in Th2 cells but not Th1 cells. Likewise, Th2 cells derived from GrB-deficient mice were resistant to TCR-ICD, and GrB deficiency or inhibition of GrB activity consequently enhanced the production of Th2 cytokines. GrB-deficient mice exhibited increased susceptibility to allergen-induced asthma. Thus, GrB plays a critical role in the TCR-ICD of Th2 cells.