Activity-dependent neuroprotective protein (ADNP) is essential for brain formation. Here, we investigated the potential neuroprotective effects of recombinant ADNP under stress conditions. The human ADNP cDNA was sub-cloned into a vector that contains VP22, a Herpes virus protein that may allow penetration of fused proteins through cellular membranes. When incubated with pheochromocytoma (PC12) cells, a neuronal model, VP22-ADNP was associated with the cells after a 25-min incubation period. Pre-incubation with VP22-ADNP enriched protein fractions protected against beta amyloid peptide toxicity and oxidative stress (H2O2) in PC12 cells. VP22 by itself was devoid of protective activity. Furthermore, the pro-apoptotic protein p53 increased by 3.5-fold from control levels in the presence of H2O2, while treatment with VP22-ADNP prior to H2O2 exposure significantly reduced the p53 protein levels. ADNP expression was previously shown to oscillate as a function of the estrus cycle in the mouse arcuate nucleus, these oscillations are now correlated with increased cellular protection.