The mechanism(s) underlying nerve growth factor (NGF)-mediated rescue of neurons from apoptosis is poorly understood, although it is well established that the high-affinity NGF receptor (TrkA) plays a pivotal role in mediating NGF effects. The report that the low-affinity NGF receptor (p75NGFR) can induce apoptosis prompted us to analyze the role played by a putative p75NGFR-associated signal-transduction element, the transcription factor nuclear factor kappa B (NFkappaB), in the modulation of apoptosis in PC12 cells. Here, we report that inhibition of NFkappaB function results in apoptosis of rat PC12 cells, a neuroblast-like cell line model of NGF-responsive neural tissues. Furthermore, NGF did not protect PC12 cells from cell death induced by the inhibition of NFkappaB. These results indicate that NFkappaB function is essential to maintain PC12 cell survival and to permit NGF-mediated rescue, consistent with the idea that signaling elements potentially associated with both TrkA- and p75NGFR are involved in the regulation of apoptosis.