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Lysosome-associated membrane glycoprotein 3 (LAMP3) is a type I transmembrane protein of the LAMP protein family with a cell-type-specific expression in alveolar type II cells in mice and hitherto unknown function. In type II pneumocytes, LAMP3 is localized in lamellar bodies, secretory organelles releasing pulmonary surfactant into the extracellular space to lower surface tension at the air/liquid interface. The physiological function of LAMP3, however, remains enigmatic. We generated Lamp3 knockout mice by CRISPR/Cas9. LAMP3 deficient mice are viable with an average life span and display regular lung function under basal conditions. The levels of a major hydrophobic protein component of pulmonary surfactant, SP-C, are strongly increased in the lung of Lamp3 knockout mice, and the lipid composition of the bronchoalveolar lavage shows mild but significant changes, resulting in alterations in surfactant functionality. In ovalbumin-induced experimental allergic asthma, the changes in lipid composition are aggravated, and LAMP3-deficient mice exert an increased airway resistance. Our data suggest a critical role of LAMP3 in the regulation of pulmonary surfactant homeostasis and normal lung function., Author summary LAMP3 is a protein of unknown molecular function with highest expression in alveolar type II cells. In alveolar type II cells, LAMP3 localizes to lamellar bodies, specific lysosome-related organelles that play an important role in secreting pulmonary surfactant, a mixture of hydrophobic proteins and lipids lowering the surface tension between the gas and the liquid phase of the lung in order to prevent alveoli from collapsing. To decipher the physiological function of LAMP3, we generated Lamp3 knockout mice, which are viable and show no apparent phenotype. Under basal conditions, both the protein and lipid composition of pulmonary surfactant are altered, but do not affect the physiological function of the lung. However, under diseased conditions of experimental allergic asthma, changes in the lipid composition are aggravated and are associated with an impaired lung function, suggesting an important role of LAMP3 in the homeostasis of pulmonary surfactant.