The present study examined brain and liver derived proteasome complexes to elucidate if there is a differential susceptibility in proteasome complexes from these tissues to undergo inactivation following exposure to oxidative stressors. It then examined the influence of ageing and dietary restriction (DR) on the observed proteasome inactivation. Studies used a filtration based methodology that allows for enrichment of proteasome complexes with less tissue than is required for traditional chromatography procedures. The results indicate that the brain has much lower levels of overall proteasome activity and exhibits increased sensitivity to hydrogen peroxide mediated inactivation as compared to proteasome complexes derived from the liver. Interestingly, the brain proteasome complexes did not appear to have increased susceptibility to 4-hydroxynonenal (HNE)-induced inactivation. Surprisingly, ageing and DR induced minimal effects on oxidative stress mediated proteasome inhibition. These results indicate that the brain not only has lower levels of proteasome activity compared to the liver, but is also more susceptible to inactivation following exposure to some (but certainly not all) oxidative stressors. This data also suggest that ageing and DR may not significantly modulate the resistance of the proteasome to inactivation in some experimental settings.