The integration of endocytic routes is critical to regulate receptor signaling. A non-clathrin endocytic pathway (NCE) of the epidermal growth factor receptor (EGFR) is activated at high ligand concentrations and targets receptors to degradation, attenuating signaling. Here we performed an unbiased molecular characterization of EGFR-NCE. We identified NCE-specific regulators, including the endoplasmic reticulum (ER)-resident protein reticulon-3 (RTN3), and a specific cargo, CD147. RTN3 was critical for EGFR/CD147-NCE, promoting the creation of plasma membrane (PM)–ER contact sites that were required for the formation/maturation of NCE invaginations. Ca 2+ release at these sites, triggered by IP3-dependent activation of ER Ca 2+ channels, was needed for the completion of EGFR internalization. Thus, we identified a mechanism of EGFR endocytosis that relies on ER-PM contact sites and local Ca 2+ signaling.