Abstract The ITAM receptors, GPVI and CLEC-2, are activated by a diversity of ligands and are targets for anti-platelet drugs. We used two-colour single-particle tracking to monitor GPVI and CLEC-2 diffusion and dimerisation in resting and stimulated CHO-K1 cells. GPVI and CLEC-2 were fluorescently labelled via SNAP and Halo tags. When expressed at ~10% of their level in platelets, GPVI and CLEC-2 are monomeric. Divalent and trivalent nanobody ligands induce GPVI and CLEC-2 homo-dimerisation, a reduction in free diffusion and an increase in immobile receptors proportionate to ligand valency. Dimers of CLEC-2 are longer-lived than those of GPVI despite a lower affinity of the monomeric nanobody that forms the backbone of the ligands. Recombinant monomeric CLEC-2 but not GPVI dimerises with an affinity (KD) of 18.5 µM. Synergy between ligand-induced crosslinking and dimerisation underlies the longer lifetime of the CLEC-2 interactions. Targeting dimerisation may be an effective way to inhibit activation of CLEC-2 by all of its ligands.