Lipids and sphingomyelinase activity were studied in spleen, liver, and brain tissues of a 13-year-old boy with Niemann-Pick disease type D (NPD-D). The greatest lipid changes occurred in spleen; cholesterol, cholesterol esters, total phospholipids, sphingomyelin, and bis-(monoacylglyceryl)phosphate were increased above normal range. In liver, striking increases were observed in cholesterol and bis-(monoacylglyceryl)phosphate. Minor changes in neutral and acidic glycolipid patterns occurred in liver, spleen, and brain. Sphingomyelinase activity (optimal at pH 5.0) was elevated above mean control levels in liver and spleen, but not in brain, kidney, or leukocytes. Enzyme properties were generally normal. Activity of NPD-D liver crude homogenate, but not that of normal liver homogenates, was inhibited at high protein concentrations. Activity levels of a second sphingomyelinase, optimal at pH 7.4, in NPD-D brain were apparently normal. These findings are generally consistent with the classification of NPD-D as a sphingomyelin lipidosis.