PI3K/Akt/mTOR signaling pathway plays an important role in cellular proliferation and growth signaling. It was demonstrated that murine models presenting activated PI3K/Akt/mTOR signaling pathway in lymphocytes develop features of systemic autoimmunity, linking this pathway to autoimmune diseases. Therefore, the goal of our study was to analyze this signaling axis in Systemic Lupus Erythematosus (SLE), the prototype of systemic autoimmune diseases, focusing on Akt and p70S6k, two components of this pathway. Our results demonstrated that both expression and phosphorylation levels of Akt are more increased in SLE than in healthy donors (HDs) CD4+ T cells suggesting an up-regulation of PI3K and mTOR activities. This result was also suggested when p70S6k, one of mTOR substrate, was evaluated. Indeed, in SLE CD4+ T cells an enhancement of p70S6k activity, in direct correlation with its expression level, was found. Since p27kip1, an inhibitor of cell cycle progression, is one of the Akt substrates, we analyzed its expression level in relationship with cell cycle progression and apoptosis. The results demonstrated that p27kip1 expression level was significantly decreased in SLE than in HDs CD4+ T cells. In SLE p27kip1 level was inversely correlated with the percentage of peripheral lymphocytes in apoptosis and in S phase of the cell cycle. Therefore, the increased activity of PI3K/Akt/mTOR signaling pathway and, as a result, the drop of p27kip1 levels observed in CD4+ T cells isolated from SLE patients might explain the accumulation of SLE lymphocytes in S and G2/M cell cycle phases where they undergo apoptosis.