The p53 family consists of p53, p63, and p73, each of which has multiple isoforms due to transcription at two separate promoters and alternative splicing. Although p53 is a bona fide tumor suppressor, p63 appears to have a Janus-faced function as a tumor suppressor and an oncogene. To address the two opposing functions of p63, we analyzed its target genes. Here, we found that GPX2, which encodes a glutathione peroxidase, is up-regulated by p63 but not p53. Accordingly, a unique responsive element was found in the promoter of the GPX2 gene that can be activated and bound by p63 but not p53. We also found that upon overexpression, GPX2 alleviates the apoptotic response of MCF7 cells to oxidative stresses. Interestingly, the protective function of GPX2 is p53 dependent. Likewise, we showed that a deficiency in GPX2 renders MCF7 cells susceptible to oxidative stress-induced apoptosis. Given that the deltaN isoform of p63 is frequently overexpressed in tumor cells, the observations here provide an insight into the mechanism by which some isoforms of p63 serve as a pro-survival factor by up-regulating GPX2 to reduce the p53-dependent oxidative stress-induced apoptotic response.