The transcriptional repressor E2F4 is important for cell cycle exit and terminal differentiation in epithelial cells, neuronal cells and adipocytes but its role in T lymphocytes proliferation and memory formation is not known. Herein, we investigated the function of E2F4 protein for the formation of functional murine memory T cells. Murine transgenic CD8+ T cells were infected in vitro with lentivirus vector expressing a shRNA targeted against E2F4 followed by in vitro stimulation with SIINFEKL antigenic peptide. For in vivo assays, transduced cells were injected into congenic mice which were then infected with HSV-OVA. The primary response, memory formation and secondary stimulation were determined for CD8+ lentivirus transduced cells. In the absence of E2F4 cell cycle repressor, activated CD8+ T cells underwent intensive proliferation in vitro and in vivo. These cells had the ability to differentiate into memory cells in vivo, but they were defective in recall proliferation. We show that transient suppression of E2F4 during CD8+ T cell priming enhances primary proliferation and has a negative effect on secondary stimulation. These findings demonstrate that the cell cycle repressor E2F4 is essential for the formation of functional memory T cells. A decrease in CD8+ T-lymphocyte compartment would diminish our capacity to control viral infections.