The present study identified SOX2 as an upstream regulator in the PI3K/Akt pathway in Ewing’s sarcoma; knockdown of SOX2 reduced expression of PI3K and abolished phosphorylation of Akt to p-Akt in vitro; whereas overexpression of Akt counteracted the variations of downstream proteins caused by silencing of SOX2, thereby negating the effects of SOX2 inhibition on the cell cycle progression and apoptosis. This evidence concerns the gene SOX2 and Ewing sarcoma.