Interactions between cytokines and Schwann cells (SC) are important in development, repair, and disorders of the peripheral nervous system (PNS). Tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta) 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 the in vitro effects of these cytokines, both singly and in combination, on cultured SC. Expression of both Type I and Type II TNF-alpha receptors was demonstrated on the SC surface by immunocytochemistry. Treatment of SC with a combination of TNF-alpha plus TGF-beta 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-alpha plus TGF-beta 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.