Leukemia is a clonal disorder with blocked normal differentiation and cell death of hematopoietic progenitorcells. Traditional modalities with most used radiation and chemotherapy are nonspecific and toxic which causeadverse effects on normal cells. Differentiation inducing therapy forcing malignant cells to undergo terminaldifferentiation has been proven to be a promising strategy. However, there is still scarce of potent differentiationinducing agents. We show here that Angelica sinensis polysaccharide (ASP), a major active component in Dongquai (Chinese Angelica sinensis), has potential differentiation inducing activity in human chronic erythromegakaryoblasticleukemia K562 cells. MTT assays and flow cytometric analysis demonstrated that ASPinhibited K562 cell proliferation and arrested the cell cycle at the G0/G1 phase. ASP also triggered K562 cellsto undergo erythroid differentiaton as revealed by morphological changes, intensive benzidine staining andhemoglobin colorimetric reaction, as well as increased expression of glycophorin A (GPA) protein. ASP inducedredistribution of STAT5 protein from the cytoplasm to the nucleus. Western blotting analysis further identifiedthat ASP markedly sensitized K562 cells to exogenous erythropoietin (EPO) by activating EPO-induced JAK2/STAT5 tyrosine phosphorylation, thus augmenting the EPO-mediated JAK2/STAT5 signaling pathway. On thebasis of these findings, we propose that ASP might be developed as a potential candidate for chronic myelogenousleukemia inducing differentiation treatment.