In the present study, we performed an extensive qualitative characterization of the platelet granule proteome using subcellular fractionation followed by mass spectrometry analysis and functional annotation. Eight-hundred-and-twenty-seven proteins were identified, most of them being associated to granules and to the granule's secretory machinery. Functional pathway analysis revealed 30 pathways, including the major histocompatibility complex class 1 (MHC I) presenting antigen pathway. This pathway was of particular interest for its potential interrelation between platelets and the immune system. Key proteins belonging to this metabolic route such as β-2-microglobulin, 26S protease regulatory subunit 10B from the proteasome and proteins 1 and 2 of the transporter associated with antigen processing were shown to co-localize with von Willebrand factor in resting platelets and to be located on the plasma membrane when platelets were activated. Key proteins of the MHC1 antigen-presenting pathway are located in platelet alpha-granules. These results suggest a possible functional role of platelet granules in platelet-related immune modulation.