To overcome the disadvantages of stem cell-based cell therapy like low cell survival at the disease site, we used stanniocalcin 2 (STC2), a family of secreted glycoprotein hormones that function to inhibit apoptosis and oxidative damage and to induce proliferation. STC2 gene was transfected into two kinds of stem cells to prolong cell survival and protect the cells from the damage by oxidative stress. The stem cells expressing STC2 exhibited increased cell viability and improved cell survival as well as elevated expression of the pluripotency and self-renewal markers (Oct4 and Nanog) under sub-lethal oxidative conditions. Up-regulation of CDK2 and CDK4 and down-regulation of cell cycle inhibitors p16 and p21 were observed after the delivery of STC2. Furthermore, STC2 transduction activated pAKT and pERK 1/2 signal pathways. Taken together, the STC2 can be used to enhance cell survival and maintain long-term stemness in therapeutic use of stem cells.