Oligodendrocytes are myelinating cells in the central nervous system that form the myelin sheath of axons to support rapid nerve conduction. Human endometrial stromal cells (EnSCs) are the abundant and easy available source for cell replacement therapy. In the present study, the EnSCs were coaxed to oligodendrocyte progenitor programming by induction of neuronal condition media, including bFGF, epidermal growth factor, and platelet-derived growth factor (PDGF)-AA signaling molecules as well as triiodothyronine. Differentiated cells were analyzed for expression of oligodendrocytic markers by quantitative reverse transcription PCR and immunocytochemistry. The results showed the expression of oligodendrocyte lineage markers such as nestin, PDGF receptor alpha (PDGFRα), Sox10, and Olig2 in the level of mRNAs. The expression of nestin and PDGFRα increased after 8 days posttreatment. Interestingly, the expression of nestin and PDGFRα genes at the levels of mRNA and proteins decreased 24 days after induction. The expression of A2B5, O4, and Olig2 proteins in EnSCs was confirmed using immunocytochemistry. The results confirmed that EnSCs could response to the signaling molecules which routinely applied for oligodendrocyte differentiation. Here for the first time, we demonstrated that EnSCs could be programmed into oligodendrocyte progenitor cells and may convince to consider these cells as suitable source for cell therapy of neurodegenerative diseases.