Manganese neurotoxicity presents with Parkinson-like symptoms that are associated with the generation of reactive oxygen species. Thus, its occurrence and severity can be reduced by cellular antioxidants. The components of the transcription factor NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway are the central regulators of cellular antioxidant responses. In this study, we investigated the role of activation of Nrf2 in response to oxidative damage induced by manganese chloride (MnCl(2)) in rat adrenal pheochromocytoma (PC12) cells. Exposure of PC12 cells to MnCl(2) for 24 h promoted an increased cytosolic and nuclear accumulation of Nrf2 and enhanced the binding of Nrf2 to the HO-1 gene ARE, thereby inducing the expression of an Nrf2-regulated gene, HO-1. Pre-treatment with tert-butylhydroquinone (tBHQ), a known agent that activates the Nrf2/ARE-HO-1 pathway, for 16 h prior to the 24 h MnCl(2) exposure attenuated both the cytotoxicity and the apoptosis induced by MnCl(2). These protective effects of tBHQ indicated a protective role for Nrf2 against MnCl(2)-induced cell damage. Taken together, these findings suggest that Nrf2 may play an important role in the protection of PC12 cells against MnCl(2) neurotoxicity.