Neocarzinostatin is an antineoplastic agent that induces differentiated morphology in human (SK-N-SH) neuroblastoma cells in culture. We have compared this morphological differentiation with that induced by the endogenous differentiation inducer, nerve growth factor (NGF), and have explored the effects of exposure to NGF upon the morphological changes induced by neocarzinostatin in SK-N-SH cells. Both NGF and neocarzinostatin induced process outgrowth in these cells. The processes formed in the presence of NGF however, were shorter and thinner than those induced by neocarzinostatin. Furthermore, only neocarzinostatin induced enlargement of the somata of the cells, and caused cell death in a concentration-dependent fraction of the culture. These distinguishing features of treated cells allowed us to determine whether or not NGF exposure altered responsiveness of the cells to neocarzinostatin. NGF (100-1000 ng/mL) protected SK-N-SH cells from the morphological and cytocidal effects of neocarzinostatin (1-hr exposure, 0.017 to 0.033 micrograms/mL). Protection from neocarzinostatin required that NGF be continuously present for a period beginning 24 hr prior to neocarzinostatin exposure and continuing for the duration of the experiment, implying that the protection afforded by NGF has a latency necessitating pretreatment, and is reversible. These results suggest that neocarzinostatin is taken up by the cells and can exert its effects once NGF is removed, even after neocarzinostatin is washed out of the medium. The signal transduction cascade triggered by NGF receptor binding may prevent the action of neocarzinostatin or the expression of the cellular changes induced in SK-N-SH cells by neocarzinostatin.