Interactions between cytokines and Schwann cells (SC) are important in development, repair, and disorders of the peripheral nervous system (PNS). Tumor necrosis factor‐α (TNF‐α) and transforming growth factor‐β (TGF‐β) are two prominent cytokines which may be involved in these processes and their gene products are upregulated in some experimental neuropathies. This study focuses on thein vitro effects of these cytokines, both singly and in combination, on cultured SC. Expression of both Type I and Type II TNF‐α receptors was demonstrated on the SC surface by immunocytochemistry. Treatment of SC with a combination of TNF‐α plus TGF‐β causes significant detachment and cell death while treatment with each cytokine alone is not significantly cytotoxic. When compared with control cultures, SC treated with the combination of cytokines exhibit an increase in the number of cells with condensed nuclei and evidence of DNA fragmentation, characteristics consistent with cells undergoing programmed cell death. Thus, TNF‐α plus TGF‐β induce SC loss of adhesion which is predominantly due to cell death. Apoptotic mechanisms are likely to contribute to some extent to this cell death. These findings provide in vitro evidence to support the hypothesis that cytokines can directly damage SC in PNS disorders. J. Neurosci. Res. 53:747–756, 1998. © 1998 Wiley‐Liss, Inc.