Sandhoff disease is caused by the defective activity of the lysosomal enzyme beta-hexosaminidase, resulting in accumulation of the glycolipids, GA2 and GM2. Niemann-Pick A/B disease is caused by the defective activity of lysosomal acid sphingomyelinase resulting in sphingomyelin accumulation. Pulmonary complications have been observed in both diseases. We now demonstrate changes in phospholipid levels in pulmonary surfactant in mouse models of these diseases. In the Hexb mouse, a model of Sandhoff disease, lipid phosphate levels were elevated in surfactant from 3- and 4-month-old mice, which was mainly due to elevated levels of phosphatidylcholine. In the ASM mouse, a model of Niemann-Pick A disease, levels of the primary storage material, sphingomyelin, were elevated as expected, and levels of phosphatidylcholine and two other phospholipids were also significantly elevated in pulmonary surfactant and in lung tissue from 5-, 6- and 7-month-old mice. These results suggest that changes in phospholipid levels and composition in lung surfactant might be a general feature of sphingolipid storage diseases, which may be in part responsible for the increased susceptibility of these patients to respiratory infections and lung pathology, often the main reason for the death of these patients.