The synaptic vesicle protein synaptotagmin was proposed to act as a major docking site for the recruitment of clathrin coats implicated in endocytosis, including the recycling of synaptic vesicles. We show here that the C2B domain of synaptotagmin binds μ2‐and α‐adaptin, two of the four subunits of the endocytic adaptor complex AP‐2. μ2 represents the major interacting subunit of AP‐2 within this complex. Its binding to synaptotagmin is mediated by a site in subdomain B that is distinct from the binding site for tyrosine‐based sorting motifs located in subdomain A. The presence of the C2B domain of synaptotagmin at the surface of liposomes enhances the recruitment of AP‐2 and clathrin. Conversely, perturbation of the interaction between synaptotagmin and AP‐2 by synprint, the cytoplasmic synaptotagmin‐binding domain of N‐type calcium channels, inhibits transferrin internalization in living cells. We conclude that a dual interaction of synaptotagmin with the clathrin adaptor AP‐2 plays a key physiological role in the nucleation of endocytic clathrin‐coated pits.