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Heparan sulfate (HS) are complex polysaccharides that reside on the plasma membrane of almost all mammalian cells, and play an important role in physiological and pathological conditions. Heparan sulfate D-glucosamine 3-O-sulfotransferase 3B1 (HS3ST3B1) participates in the last biosynthetic steps of HS and transfers sulfate to the 3-O-position of glucosamine residues to yield mature sugar chains. To date very few biological processes or proteins have been described that are modulated by HS3ST3B1. In this study, we observed that HS3ST3B1 positively contributed to acute myeloid leukemia (AML) progression in vitro and in vivo, and these activities were associated with an induction of the proangiogenic factor VEGF expression and shedding. Moreover, the effects of HS3ST3B1 on VEGF release can be attenuated after treatment of heparanase inhibitor suramin, which prevented VEGF secretion and subsequently blocked VEGF-induced activation of ERK and AKT, suggesting that 3-O-sulfation of HS by HS3ST3B1 facilitated VEGF shedding; the effects of HS3ST3B1 on activation of ERK and AKT can also be blocked by VEGFR inhibitor axitinib, suggestive of a relationship between 3-O-sulfation of HS and VEGF-activated signaling pathways. Taken together, our findings support that VEGF is an important functional target of HS3ST3B1 and provide a new mechanism of HS3ST3B1 in AML.