Contact inhibition (CI) is an important tumor-suppressive mechanism that arrests cell cycle when cells reach high density. Indeed, CI is aberrantly absent in cancer cells and the dysregulation of this can contribute to tumorigenesis. Previously, it has been shown that reactive oxygen species (ROS) levels are repressed at high cell density, which is required for CI, but no molecular mechanism of this ROS regulation has been reported. Here, we show that PGC1 alpha regulates cell density-dependent Cl. PGC1 alpha, is markedly induced in response to high cell density and suppresses ROS production. Although cellular ROS levels are progressively decreased with increasing cell density, knockdown of PGC1 alpha results in a defect of density-dependent ROS suppression. Importantly, PGC1 alpha knockdown cells become less sensitive to high cell density and exhibit loss of Cl. Mechanistically, PGC1 alpha represses ROS production by inducing mitochondrial SIRT3, and thus SIRT3 overexpression rescues the defects of CI by PGC1 alpha knockdown. These results demonstrate that mitochondrial ROS production is a crucial regulator of cell proliferation and identify a new role of PGC1 alpha in Cl. (C) 2018 Elsevier Inc. All rights reserved.