We report here that exposure to low concentrations of proteasome inhibitors (e.g. 10–100 nm MG-132, 0.1–3 nm epoxomicin or 10–30 nmclasto-lactacystin β-lactone) resulted in an enhancement, rather than an inhibition, of proteasome activity in cultured neocortical neurons. Size-fractionation chromatography confirmed that the enhanced peptide cleavage activity was associated with proteasome-sized complexes. This sub toxic exposure reduced neuronal death caused by subsequent exposure to oxidative stress (100–200 µm H2O2 for 30 min, 24-h exposure to 100 µm paraquat or 7.5 µm menadione), but did not alter vulnerability to excitotoxicity (5-min exposure to 30–100 µm NMDA or 24 exposure to 12 µm NMDA). Sub toxic proteasome inhibitor exposure caused an increase in levels of proteasome core subunit proteins and mRNAs, but not in levels of potentially cytoprotective heat shock proteins (hsp70, hsp90 and hsp40). The neuroprotective effects of proteasome inhibitor pre-treatment were blocked by coapplication of proteasome inhibitors during the oxidative insult. These findings support a model in which sublethal proteasome inhibition induces neurons to increase proteasome activity and promotes resistance to oxidative injury and suggests that enhancement of proteasome activity is a potential therapeutic target for diseases in which oxidative stress has been implicated.