Stress‐induced activation of an acidic sphingomyelinase leading to generation of ceramide, an important lipid mediator, has been associated with apoptosis; however, the implication of this hydrolase has been questioned. The present study aimed at re‐evaluating the role of this lysosomal enzyme in apoptosis initiated by different apoptotic inducers. The sensitivity of a series of acid sphingomyelinase‐deficient cell lines derived from Niemann‐Pick disease patients to stress‐induced apoptosis was investigated. We have now shown that stress stimuli, such as anthracyclines, ionizing radiation, and Fas ligation trigger similar apoptotic hallmarks in normal and acid sphingomyelinase‐deficient cell lines. Retrovirus‐mediated gene correction of enzyme deficiency in Niemann‐Pick cells does not modify response to apoptosis. Ceramide production is comparable in normal and Niemann‐Pick cells, and increased activity of neutral sphingomyelinase is observed. Thus, our findings cast serious doubts that lysosomal sphingomyelinase activation is responsible for stress‐induced apoptosis of cultured cells.