Tumor suppressor p53 maintains genome stability by differentially activating target genes that control diverse cellular responses, such as the antioxidant response, cell cycle arrest and apoptosis. Despite the fact that many p53 downstream genes have been well characterized, novel p53 target genes are continuously being identified. Here, we report that Tpt1 is a direct target gene of p53. We found that p53 upregulates the transcription of Tpt1 and identified a p53-responsive element in the promoter of the mouse Tpt1 gene. Furthermore, p53-dependent induction of Tpt1 was able to reduce oxidative stress, minimize apoptosis, and promote cell survival in response to H2O2 challenge. In addition, a positive correlation between the expression of p53 and Tpt1 only existed in normal lung tissues, not in lung tumors. Such positive correlation was also found in lung cell lines that contain wild-type p53, but not mutated p53. Based on the important role of Tpt1 in cancer development, chemoresistance, and cancer reversion, identification of Tpt1 as a direct target gene of p53 not only adds to the complexity of the p53 network, but may also open up a new avenue for cancer prevention and intervention.