Previous reports have indicated that the use of δ agonists may prove to be a viable therapeutic tool as an analgesic agent without conventional opioid side effects. In addition, recent evidence suggests that δ ligands may exert neuroprotective effects under a variety of toxin insults. The aim of the present studies was to assess the ability of δ agonists (peptide: [D-Pen 2,5 ] enkephalin (DPDPE), non-peptide: (+)-4-[(aR)-a-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC-80)) and antagonists (naltrindole) to modify dichlorofluorescein (DCFH) fluorescence in the presence of the peroxynitrite generator, 3-morpholinylsydnoneimine chloride (SIN-1) or HIV-protein, TAT 1–72 (TAT) in SK-N-SH cells. Both DPDPE (100nM) and SNC-80 (250nM) attenuated (30–50%) the increased oxidative stress in the presence of SIN-1. This effect was partially reversed by addition of naltrindole, suggesting involvement of δ receptors. Peroxynitrite radicals are involved in neurotoxicity associated with TAT. Incubation with TAT (10–250nM) demonstrated a concentration-dependent increase in oxidative stress up to 200% over control values. Preincubation with δ agonists reduced 50nM TAT-mediated oxidative stress 15–40%, which was partially reversed by naltrindole. Increasing log-concentrations of DPDPE or SNC-80 (0.01–100μM) attenuated TAT-mediated oxidative stress up to 50% at 100μM. In conclusion, these data demonstrate that both peptide and non-peptide delta agonists can partially attenuate intracellular oxidative stress, in part through a receptor-mediated mechanism. This suggests that delta ligands may have therapeutic usefulness in HIV patients beyond analgesia.