Collaborative interactions between Th cells and B cells are necessary for the production of antibody responses to most protein antigens and for the generation of memory B cells in germinal centers (GCs). Although it is well established that Th cells are pivotal for the GC reaction, the mechanisms that control the homeostasis of Th cells during the GC response remain largely unknown. Here we show that, unlike other effector T cells, a significant number of CD4+CD45RO+CD57+ T cells, which are the major Th cells residing in the GCs, are undergoing apoptosis in vivo. CD4+CD45RO+CD57+ GC T cells exhibit similar sensitivities to apoptotic signals and to caspase inhibitors as immature thymocytes. Moreover, CD4+CD45RO+CD57+ GC T cells express a unique profile of genes that control apoptosis and cell cycle, providing possible molecular mechanisms for the high rates of apoptotic death of these Th cells in the GCs.