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Summary: To slow down the coronavirus disease 2019 (COVID‐19) pandemic an unequalled vaccination campaign was initiated. Despite proven efficacy and safety, a rare but potentially fatal complication of adenoviral‐vector vaccines, called vaccine‐induced immune thrombotic thrombocytopenia (VITT), has emerged the pathogenesis of which seems to be related to the development of platelet‐activating anti‐platelet factor 4 (PF4) antibodies. While a few studies have evaluated the incidence of anti‐PF4 positivity in anti‐severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) vaccine recipients, to date no studies have assessed whether an antiplatelet immunological response develops and if this associates with platelet and blood clotting activation. We carried out a prospective study in healthy subjects who received the first dose of ChAdOx1 or Ad26.COV2.S or BNT162b2 vaccines to evaluate platelet‐specific and non‐specific immune response and in vivo platelet activation and blood clotting activation. Individuals receiving ChAdOx1 and, less so, Ad26.COV2.S developed with high frequency auto‐ or alloantiplatelet antibodies, increased circulating platelet‐derived microvesicles and soluble P‐selectin associated with mild blood clotting activation. Our study shows that an immunological reaction involving platelets is not uncommon in individuals receiving anti‐SARS‐CoV‐2 vaccination, especially after ChAdOx1 and Ad26.COV2.S, and that it associates with in vivo platelet and blood clotting activation. [ABSTRACT FROM AUTHOR]