Updated project metadata. Sjögren’s disease (SjD) is an autoimmune disease that affects exocrine tissues and is characterized by increased apoptosis and decreased expression of membrane proteins involved in secretory function, such as Na-K-Cl cotransporter-1 (NKCC1), in salivary and lacrimal glands. Although the pathogenic mechanism triggering SjD is not well understood, overexpression of lysosome-associated membrane protein 3 (LAMP3) is associated with the disease in a subset of SjD patients and the development of SjD-like phenotype in mice. In this study, histological analysis of minor salivary glands of SjD patients suggested that LAMP3-containing material is being ejected from cells. Follow-on in vitro experiments with cells exposed to larger extracellular vesicles (LEVs) derived from LAMP3-overexpressing cells showed increased apoptosis and decreased NKCC1 expression. Proteomics identified LAMP3 as a major component of LEVs derived from LAMP3-overexpressing cells. Live-cell imaging visualized release and uptake of LAMP3-containing LEVs from LAMP3-overexpressing cells to naïve cells. Furthermore, experiments with recombinant LAMP3 protein alone or complexed with Xfect protein transfection reagent demonstrated that internalization of LAMP3 was required for apoptosis in a caspase-dependent pathway. Taken together, we identified a new role for extracellular LAMP3 in cell-to-cell communication via LEVs, which provides further support for targeting LAMP3 as a therapeutic approach in SjD.