Periodontal ligament stem cells (PDLSCs) are promising stem cells sources for regenerative medicine, particularly clinical periodontal ligament repair. It is critical to maintain high quality and a large quantity of PDLSCs for clinical usage. However, how PDLSCs respond to environmental stimuli, including reactive oxygen species (ROS), is poorly understood. The aim of the present study was to investigate how PDLSCs react to oxidative stress and the underlying mechanisms. Hydrogen peroxideinduced oxidative stress was used to mimic a ROS increase in rat PDLSCs. The expression levels of Creb were detected under oxidative stress to examine the role that Creb serves in PDLSCs under oxidative stress. The present results demonstrated that the expression of Creb was reduced in a dosedependent manner in response to the H2O2 stimulus. Overexpressing Creb significantly reduced the ROS levels and protein expression levels of apoptotic genes in PDLSCs. The phosphorylation of the ERK pathway is indispensable in the activation of Crebinduced protection. Our results revealed a protective role of Creb in ROSinduced apoptosis, and validated the ERK/Creb/apoptosis regulator Bcl2 pathway works as an antiapoptotic signaling in PDLSCs. These findings will facilitate the in vitro culturing of PDLSCs for clinical usage and promote stem cell based therapy for periodontal tissue regeneration.