Although contact inhibition is a fundamental process for multicellular organisms, how proliferation is inhibited at high cellular densities remains poorly characterized. Here we show that 4E-BP1, one major repressor of cap-dependent translation, plays a critical role in density-mediated cell cycle arrest. 4E-BP1 promoter is activated and 4E-BP1 protein amount increases as cells reach confluence. Conversely, a much less marked density-dependent inhibition of cell proliferation is observed upon 4E-BP1 silencing. We further show that at high density, progression through the G₁ phase of the cell cycle is faster and Cyclin D1 protein is induced in different cell types where 4E-BP1 has been either downregulated (stable shRNA expression or transient siRNA transfection) or removed (knock-out). Thus 4E-BP1 appears as an important mediator of contact inhibition.