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Abstract only Heparan sulfate has many biological activities, in particular positive effects on growth factor signaling and cell adhesion. Thus, mutations in heparan sulfate assembly typically manifest in loss‐of‐function, leading to developmental defects or altered physiology. Here, we demonstrate that genetic and pharmacological reduction of heparan sulfate enhances wound healing, a gain‐of‐function phenotype. In one model, 8‐week‐old mice were shaved and subjected to a full thickness 6‐mm diameter punch biopsy through the dorsal skin. Imaging of the wound over two weeks showed that wound closure occurred more rapidly in mice bearing a defect in Ext gene function, which encodes the copolymerase responsible for the assembly of the backbone of the chain. Enhanced wound closure also occurred after tamoxifen‐induced deficiency of heparan sulfate in skin (Rosa26‐Cre ER ; Ext1 flox/flox mice) or in keratinocytes (K14‐Cre ER ; Ext1 flox/fflox ). Wildtype mice treated orally with xyloside also showed significant enhancement in dermal wound repair. We conclude that manipulation of the levels of heparan sulfate in vivo increases the capacity for wound repair, suggesting a novel approach for enhancing the regenerative property of tissues.