Epithelial cell adhesion molecule (EpCAM) was reported to be cleaved into extracellular domain of EpCAM (EpEX) and intracellular domain of EpCAM (EpICD). We previously reported that EpCAM serves as a potent stem cell marker which is highly and selectively expressed by undifferentiated rather than differentiated hESC. However， the functional role of EpCAM remains elusive. Here， we found that EpEX and EpCAM enhance the efficiency of OSKM reprogramming. Interestingly， Oct4 or Klf4 alone， but not Sox2， can successfully reprogram fibroblasts into iPSCs with EpEX and EpCAM. Moreover， EpEX and EpCAM trigger reprogramming via activation of STAT3， which leads to the nuclear-translocation of HIF2α. This study reveals the importance of a novel EpEX/EpCAM-STAT3-HIF2α signal in the reprogramming process， and uncovers a new means of triggering reprogramming by delivery of soluble and transmembrane proteins.