The cyclic AMP-responsive element binding protein (CREB) is a posttranslationally activated transcription factor that has been implicated in numerous brain functions including cell survival. In this study we investigated whether CREB overexpression using transient transfection of a pAAV/CMV-CREB plasmid altered neuronal cells' susceptibility to apoptosis. We found that elevated CREB protein inhibited apoptosis induced by okadaic acid. At least part of this effect is critically dependent on prolonged Ser133 phosphorylation, as a directed mutation at this site decreased CREB-induced protection. These results suggest that CREB is a survival factor for neuronal cells and that treatments aimed at augmenting CREB phosphorylation in the brain may be neuroprotective.