ABSTRACT.Cultured skin fibroblast homogenates from patients with Niemann-Pick disease Type C, were able to degrade sphingomyelin liposomes at a normal rate. Fibroblasts from patients with Niemann-Pick disease Types A and B were less active (0.08–0.55 versus 0.96–2.93 nmol/ h/mg). When fibroblasts were maintained in synthetic media (MCDB-104) devoid of fetal calf serum for a period of 21 days, sphingomyelinase activity measured at pH 3.8 increased in control and Niemann-Pick Type C (up to 15-fold) and in Niemann-Pick Type B (up to 3-fold) while Niemann-Pick Type A showed no significant increase in sphingomyelinase activity.Addition of a protein activator isolated from the spleen of a Type I Gaucher's disease patient stimulated a 2–7.5-fold increase in sphingomyelinase activity in normal, Niemann-Pick Type B and C fibroblasts, while under the same conditions the Niemann-Pick Type A fibroblast enzyme responded poorly.Our data show that the residual sphingomyelinase activity in Niemann-Pick Type A can be differentiated from that present in other phenotypic forms by its lack of response to the Gaucher activator. Furthermore, we can find no evidence to support the view that Niemann-Pick Type C sphingomyelinase differs from the normal enzyme in its response to Gaucher activator.