Transforming growth factor alpha (TGF alpha) is a mitogenic polypeptide that is structurally homologous to epidermal growth factor (EGF) and appears to bind to the same receptor in all systems tested previously. In the present study, TGF alpha was found to enhance survival and neurite outgrowth of cultured neonatal rat dorsal root ganglion (DRG) neurons in a dose-dependent manner. This effect was observed with TGF alpha concentrations as low as 17.8 pM. By contrast, EGF at concentrations up to 83 nM was ineffective. Moreover, EGF did not antagonize the TGF alpha survival-promoting effect unless present in large excess (500-fold the concentration for which TGF alpha is effective); even in this case, only partial antagonism was achieved. Survival of neurons from nodose, trigeminal, and sympathetic ganglia was not increased by TGF alpha. Both a subpopulation of DRG neurons and of macrophages in the cultures bound iodinated TGF alpha. This binding was inhibited by excess unlabeled TGF alpha but not EGF. Our data are consistent with the possibilities that the actions of TGF alpha on DRG neurons occur indirectly via unidentified neurotrophic molecules other than NGF as well as directly on the neurons themselves. Thus, TGF alpha, in contrast to EGF, may act as a survival or maintenance factor for a subset of rat sensory neurons. Mediation of this neurotrophic effect appears to occur via a new form of TGF alpha receptor.