Myoferlin is a member of the ferlin family of proteins that promotes endomembrane fusion with the plasma membrane in muscle cells and endothelial cells (EC). In addition, myoferlin is necessary for the surface expression of vascular endothelial growth factor (VEGF) receptor-2 through the formation of a protein complex with dynamin-2 (Dyn-2). Since Dyn-2 is necessary for the fission of endocytic vesicles from the plasma membrane, we tested the hypothesis that myoferlin may regulates aspects of receptor-dependent endocytosis. Here we show that myoferlin gene silencing decreases both clathrin and caveolae/raft dependent endocytosis, whereas ectopic myoferlin expression in COS-7 cells increases endocytosis by up to 125%. The genetic loss of myoferlin reduces receptor-mediated endocytosis in intact blood vessels, supporting the in vitro data. Inhibition of Dyn-2 activity impairs endocytosis as well as membrane resealing after injury, indicating that Dyn-2 also participates in both membrane fission and fusion processes. Mechanistically, myoferlin partially co-localizes with Dyn-2 and forms a protein complex with Cav-1 solubilized from tissue extracts. Together, these data describe a new role for myoferlin in receptor-dependent endocytosis and an overlapping role for myoferlin-Dyn-2-Cav-1 protein complexes in membrane fusion and fission events.