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Although vascular endothelial growth factor (VEGF) has been delivered to critical\u2010size bone defect models to augment blood vessel infiltration into the defect area, its potential to increase bone repair remains ambiguous. In this study, we investigated whether integrin\u2010specific biomaterials modulate the effects of VEGF on bone regeneration. We engineered protease\u2010degradable, VEGF\u2010loaded poly(ethylene glycol) (PEG) hydrogels functionalized with either a triple\u2010helical, \u03b1<jats:sub>2<\/jats:sub>\u03b2<jats:sub>1<\/jats:sub>integrin\u2010specific peptide GGYGGGP(GPP)<jats:sub>5<\/jats:sub>GFOGER(GPP)<jats:sub>5<\/jats:sub>GPC (GFOGER) or an \u03b1<jats:sub>v<\/jats:sub>\u03b2<jats:sub>3<\/jats:sub>integrin\u2010targeting peptide GRGDSPC (RGD). Covalent incorporation of VEGF into the PEG hydrogel allowed for protease degradation\u2010dependent release of the protein while maintaining VEGF bioactivity. When applied to critical\u2010size segmental defects in the murine radius, GFOGER\u2010functionalized VEGF\u2010free hydrogels exhibited significantly increased vascular volume and density and resulted in a larger number of thicker blood vessels compared to RGD\u2010functionalized VEGF\u2010free hydrogels. VEGF\u2010loaded RGD hydrogels increased vascularization compared to VEGF\u2010free RGD hydrogels, but the levels of vascularization for these VEGF\u2010containing RGD hydrogels were similar to those of VEGF\u2010free GFOGER hydrogels. VEGF transiently increased bone regeneration in RGD hydrogels but had no effect at later time points. In GFOGER hydrogels, VEGF did not show an effect on bone regeneration. However, VEGF\u2010free GFOGER hydrogels resulted in increased bone regeneration compared to VEGF\u2010free RGD hydrogels. These findings demonstrate the importance of integrin\u2010specificity in engineering constructs for vascularization and associated bone regeneration. \u00a9 2016 Wiley Periodicals, Inc. 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