Reactive oxygen species (ROS) act as both signaling molecules and mediators of cell damage in the nervous system and are implicated in the pathogenesis of neurodegenerative diseases. Neurotrophic factors such as the nerve-derived growth factor (NGF) support neuronal survival during development and promote regeneration after neuronal injury through the activation of intracellular signals whose molecular effectors and downstream targets are still largely unknown. Here we present evidence that early oxidative signals initiated by NGF in PC12 cells, an NGF-responsive cell line, play a critical role in preventing apoptosis induced by serum deprivation. This redox-signaling cascade involves phosphatidylinositol 3-kinase, the small GTPase Rac-1, and the transcription factor cAMP-responsive element-binding protein (CREB), a molecule essential to promote NGF-dependent survival. We found that ROS are necessary for NGF-dependent phosphorylation of CREB, an event directly correlated with CREB activity, whereas hydrogen peroxide induces a robust CREB phosphorylation. Cells exposed to NGF show a late decrease in the intracellular content of ROS when compared with untreated cells and increased expression of the mitochondrial antioxidant enzyme manganese superoxide dismutase, a general inhibitor of cell death. Accordingly, serum deprivation-induced apoptosis was selectively inhibited by low concentrations of the mitochondrially targeted antioxidant Mito Q (mitoquinol/mitoquinone). Taken together, these data demonstrate that the oxidant-dependent activation of CREB is a component of NGF survival signaling in PC12 cells and outline an intriguing circuitry by which a cytosolic redox cascade promotes cell survival at least in part by increasing mitochondrial resistance to oxidative stress.