Platelets use SNARE‐mediated exocytosis to maintain hemostasis and thrombosis. These processes are maintained by the exocytosis of platelet releasate from the three types of granules in platelets: dense, alpha, and lysosomal. Understanding how the process of exocytosis is regulated in secretion, we look for potential SNARE regulators and found the protein α‐synuclein. α‐Synuclein appears to be the only member of the synuclein family present in platelets and is very abundant. To address the role of α‐synuclein in platelets, we examined the hemostatic phenotype of α‐synuclein−/− mice. Using a tail‐bleeding time assay, we observed that α‐synuclein−/− mice bleed for a slightly longer time compared to the wild‐type mice, suggesting a platelet granule secretion defect. Secretion kinetic and dose‐response assays showed that platelets from α‐synuclein−/− mice have defective release from the dense granules and less so from lysosomal granules. To understand the mechanism of this defect, we asked whether α‐synuclein is acting as a VAMP‐chaperone in platelets and thus modulates secretion by controlling V‐SNARE levels. The two dominant T‐SNARES SNAP‐23 and Syntaxin‐11 are not altered in α‐synuclein−/− mice. However, the dominant V‐SNARE VAMP‐8 was reduced. Other V‐SNARES in the α‐synuclein−/− mice VAMP‐2, VAMP‐3, and VAMP‐7 were normal. Additional western blotting experiments demonstrated the presence of the α‐synuclein‐interactor Cysteine String Protein, further identifying elements of the platelet secretory machinery. These experiments demonstrate a role for α‐synuclein in platelet exocytosis and hemostasis and will further fill a gap in our knowledge on α‐synuclein’s physiological function and understanding how the process of exocytosis is regulated.Support or Funding InformationThis work was supported by a grant from the National Institutes of Health, National Heart, Lung, and Blood Institute (HL56652) and a Veterans Affairs Merit Award to S.W.W.