Myelin biogenesis is a complex process involving coordinated exocytosis, endocytosis, mRNA transport and cytoskeletal dynamics.While abnormalities of myelin are common in lysosomal storage diseases, our understanding of the role of lysosomes in the formation and maintenance of myelin is still limited.Here we show that lysosomes in Schwann cells contain abundant myelin protein P0, which accounts for over half the total protein of compact myelin in the peripheral nervous system, and exhibit Ca2+-dependent exocytosis in response to various stimuli.Down regulation of Rab27a, a small GTPase required for the trafficking of the secretory lysosomes to the plasma membrane, largely blocked lysosomal exocytosis in Schwann cells and inhibited the re-myelination of regenerated sciatic nerve.These findings highlight a novel role for lysosomes in Schwann cells and suggest that the regulated lysosome exocytosis in Schwann cells may have important physiological and pathological significance in the peripheral nervous system.