Impairment in ubiquitin-proteasome system has been shown to be implicated in the pathogenesis in neurodegenerative disorders, such as Parkinson's disease. Flavonoid baicalein has demonstrated anti-oxidant and anti-inflammatory effects. However, the effect of baicalein on the neuronal cell death due to proteasome inhibition has not been studied. Thus, in the respect of the cell death process, we assessed the effect of baicalein on the proteasome inhibition-induced apoptosis using differentiated PC12 cells. The proteasome inhibitors MG132 and MG115 induced a decrease in Bid, Bcl-2, Bcl-xL and survivin protein levels, an increase in Bax levels, loss of the mitochondrial transmembrane potential, release of cytochrome c, activation of caspases (-8, -9 and -3), an increase in the tumor suppressor p53 levels and cleavage of PARP-1. Baicalein attenuated the proteasome inhibition-induced changes in the levels of apoptosis-related proteins, formation of reactive oxygen species, depletion of GSH, DNA damage and cell death. The results show that baicalein may attenuate the proteasome inhibition-induced apoptosis in PC12 cells by suppressing the activation of the mitochondrial pathway and the caspase-8- and Bid-dependent pathways. The preventive effect appears to be attributed to its inhibitory effect on the formation of reactive oxygen species and depletion of GSH.