Neuroblastomas are histopathologically heterogeneous, ranging from immature malignant tumors to benign ganglioneuromas. The amount of Schwann cell stroma greatly increases with neuroblastoma differentiation, and these Schwann cells appear to be normal cells that infiltrate the tumor. To determine whether Schwann cells influence neuroblast differentiation, four human neuroblastoma cell lines were cultured in the presence or absence of human Schwann cell-conditioned medium for 7 days. Neuroblastoma cell survival, as determined by a colorimetric assay, more than doubled in three of the four neuroblastoma cell lines in the Schwann cell-conditioned medium. There was a corresponding reduction in apoptosis as measured by a nick-end labeling assay, with little change in mitotic rate. Schwann cell-conditioned medium induced extensive neurite outgrowth in all of the neuroblastoma cell lines, and these processes contained mature neurofilament in three of the cell lines. These results indicate that Schwann cells produce soluble substances capable of supporting survival and differentiation in neuroblastoma cell lines. This may represent a biological mechanism responsible for neuronal differentiation in stroma-rich neuroblastomas.