Activation-induced cell death (AICD) plays an important role in maintenance of peripheral lymphocyte homeostasis. Reactive oxygen species (ROS) combined with simultaneous calcium (Ca2+) influx into the cytosol are required for induction of AICD. The extract obtained from the stem bark of Mangifera indica L. has shown to protect T cells from in vitro AICD. This extract is rich in polyphenolic compounds, the three main components of which are mangiferin (MA), catechin (C) and epicatechin (EC). The present study has focused on the possible contribution of the polyphenols MA, C and EC to the demonstrated protective effect of M. indica extract on in vitro human T cell AICD. Our results show that these polyphenols diminished the increase of intracellular ROS and free Ca2+ induced by T cell receptor (TCR) triggering. In addition, these polyphenols attenuated AICD. Our findings suggest that the T cell survival effect of M. indica extract is mediated, at least in part, by its main polyphenols.