Upon antigen stimulation, lymphocytes enter in cell cycle and proliferate, and most of the activated T cells die by apoptosis. Many of the proteins that regulate lymphocyte activation are Under the control of transcription factors belonging to the NFAT family. As previously demonstrated, NFATC2-/- mice consistently showed a marked increase in lymphocyte proliferation. Here, we evaluate the role of NFATC2 in regulating lymphocyte proliferation and its involvement in the control of cell cycle progression during lymphocyte activation. NFATC2-/- lymphocytes, including CD4+ T cells and B cells, hyperproliferated upon stimulation when compared with NFATC2+/+ cells. Analysis of cell death demonstrated that NFATC2-/- lymphocytes displayed an increased rate of apoptosis after antigen stimulation in addition to the hyperproliferation. Cell cycle analysis after antigen stimulation showed that NFATC2-/- cultures contained more cycling cells when compared with NFATC2+/+ cultures, which is related to a shortening in time of cell division upon activation. Furthermore, hyperproliferation of NFATC2-/- lymphocytes is correlated to an overexpression of cyclins A2, B1, E, and F. Taken together, our results suggest that the NFATC2 transcription factor plays an important role in the control of cell cycle during lymphocyte activation and may act as an inhibitor of cell proliferation in normal cells.