ORAI1 is a pore subunit of Ca 2+ release-activated Ca 2+ channels that mediate TCR stimulation-induced Ca 2+ entry. A point mutation in ORAI1 (ORAI1 R91W) causes SCID in human patients that is recapitulated in Orai1−/− mice, emphasizing its important role in the immune cells. In this study, we have characterized a novel function of ORAI1 in T cell death. CD4+ T cells from Orai1−/− mice showed robust proliferation with repetitive stimulations and strong resistance to stimulation-induced cell death due to reduced mitochondrial Ca 2+ uptake and altered gene expression of proapoptotic and antiapoptotic molecules (eg, Fas ligand, Noxa, and Mcl-1). Nuclear accumulation of NFAT was severely reduced in ORAI1-deficient T cells, and expression of ORAI1 and a constitutively active mutant of NFAT recovered cell death. These results indicate NFAT-mediated cell death pathway as one of the major downstream targets of ORAI1-induced Ca 2+ entry. By expressing various mutants of ORAI1 in wild-type and Orai1−/− T cells to generate different levels of intracellular Ca 2+, we have shown that activation-induced cell death is directly proportional to the intracellular Ca 2+ concentration levels. Consistent with the in vitro results, Orai1−/− mice showed strong resistance to T cell depletion induced by injection of anti-CD3 Ab. Furthermore, ORAI1-deficient T cells showed enhanced survival after adoptive transfer into immunocompromised hosts. Thus, our results demonstrate a crucial role of the ORAI1–NFAT pathway in T cell death and highlight the important role of ORAI1 as a major route of Ca 2+ entry during activated T cell death.