VEGF‐A (VEGF) drives angiogenesis through activation of downstream effectors to promote endothelial cell proliferation and migration. Although VEGF binds both VEGF receptor 1 (R1) and receptor 2 (R2), its proangiogenic effects are attributed to R2. Secreted protein, acidic, rich in cysteine (SPARC) is a matricellular glycoprotein thought to inhibit angiogenesis by preventing VEGF from activating R1, but not R2. Because R2 rather than R1 mediates proangiogenic activities of VEGF, the role of human SPARC in angiogenesis was reevaluated. We confirm that association of SPARC with VEGF inhibits VEGF‐induced HUVEC adherence, motility, and proliferation in vitro and blocks VEGF‐induced blood vessel formation ex vivo. SPARC decreases VEGF‐induced phosphorylation of R2 and downstream effectors ERK, Akt, and p38 MAPK as shown by Western blot and /or phosphoflow analysis. Surface plasmon resonance indicates that SPARC binds slowly to VEGF (0.865 ± 0.02 × 10⁴ M^‐1s^‐1)with a K_d of 150 nM, forming a stable complex that dissociates slowly (1.26 ± 0.003 × 10^‐3 s^‐1). Only domain III of SPARC binds VEGF, exhibiting a 15‐fold higher affinity than full‐length SPARC. These findings support a model whereby SPARC regulates angiogenesis by sequestering VEGF, thus restricting the activation of R2 and the subsequent activation of downstream targets critical for endothelial cell functions.— Cydzik, M., Abdul‐Wahid, A., Park, S., Bourdeau, A., Bowden, K., Prodeus, A., Kollara, A., Brown, T. J., Ringuette, M. J., Gariépy, J. Slow binding kinetics of secreted protein, acidic, rich in cysteine‐VEGF interaction limit VEGF activation of VEGF receptor 2 and attenuate angiogenesis. FASEB J. 29, 3493‐3505 (2015). www.fasebj.org