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Summary To enhance the antithrombotic properties of recombinant glycoprotein VI fragment crystallizable (GPVI-Fc), the authors incubated GPVI-Fc with anti-human Fc antibodies to cross-link the Fc tails of GPVI-Fc. Cross-linking potentiated the inhibition of human plaque- and collagen-induced platelet aggregation by GPVI-Fc under static and flow conditions without increasing bleeding time in vitro. Cross-linking with anti-human-Fc Fab2 was even superior to anti-human-Fc immunoglobulin G (IgG). Advanced optical imaging revealed a continuous sheath-like coverage of collagen fibers by cross-linked GPVI-Fc complexes. Cross-linking of GPVI into oligomeric complexes provides a new, highly effective, and probably safe antithrombotic treatment as it suppresses platelet GPVI-plaque interaction selectively at the site of acute atherothrombosis., Visual Abstract, Highlights • The GPVI collagen receptor mediates platelet activation to collagen exposed after rupture or injury of atherosclerotic plaques. Revacept®, a GPVI-Fc fusion protein binding to plaque collagen and concealing binding sites for platelet GPVI, acts as a lesion-focused antiplatelet drug. To optimize its specific inhibition of plaque-induced platelet activation, we cross-linked the Fc tails of GPVI-Fc with anti-human-Fc IgG or Fab2 antibodies. • Cross-linking yielded oligomeric GPVI-Fc complexes, which inhibited atherosclerotic plaque- induced platelet aggregation in static and flow assays as efficiently as antibodies blocking GPVI receptors on platelets. Under arterial flow, GPVI-Fc cross-linking with anti-Fc-Fab2 was superior to cross-linking with anti-Fc IgG. • Advanced optical imaging revealed a rapid and stable sheath-like coverage of collagen fibers by cross-linked GPVI-Fc complexes preventing platelet attachment to collagen. • Cross-linked GPVI-Fc did not increase bleeding time in vitro. • Transformation of GPVI into multivalent GPVI complexes may provide a new superior strategy to suppress atherothrombosis without increasing systemic bleeding risk.