Selected clones of the sympathetic precursor-like cell line PC12 (rCl8) are resistant to oxidative cell death induced by the Alzheimer’s disease-associated amyloid β protein (Aβ) and hydrogen peroxide (H₂O₂). Here, we show that the transcriptional activity and DNA binding activity of the redox-sensitive transcription factor NF-κB and its nuclear expression are constitutively increased in rCl8 cells compared with their nonresistant parental PC12 cell (PC12p) counterpart. Suppression of the transcriptional activity of NF-κB in rCl8 cells with the synthetic glucocorticoid dexamethasone or by direct overexpression of a super-repressor mutant form of IκBα, a specific inhibitor of NF-κB, reversed the oxidative stress resistance phenotype of these cells and ultimately led to increased cell death after the challenge with H₂O₂. Dexamethasone treatment also caused an increase in the protein level of IκBα. Our data show that an increased baseline of NF-κB activity may mediate the resistance of these cells of neuronal origin to oxidative stress. Therefore, the presented model may help to identify possible neuronal target genes of NF-κB and to further elucidate the molecular basis of the differential sensitivity of neurons in neurodegenerative conditions associated with an increased oxidative burden, such as in Alzheimer’s disease.