Neural injury leads to inflammation and activation of microglia that in turn may participate in progression of neurodegeneration. The mechanisms involved in changing microglial activity from beneficial to chronic detrimental neuroinflammation are not known but reactive oxygen species (ROS) may be involved. We have addressed this question in Nrf2‐knockout mice, with hypersensitivity to oxidative stress, submitted to daily inoculation of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) for 4 weeks. Basal ganglia of these mice exhibited a more severe dopaminergic dysfunction than wild type littermates in response to MPTP. The amount of CD11b‐positive/CD45‐highly‐stained cells, indicative of peripheral macrophage infiltration, did not increase significantly in response to MPTP. However, Nrf2‐deficient mice exhibited more astrogliosis and microgliosis as determined by an increase in messenger RNA and protein levels for GFAP and F4/80, respectively. Inflammation markers characteristic of classical microglial activation, COX‐2, iNOS, IL‐6, and TNF‐α were also increased and, at the same time, anti‐inflammatory markers attributable to alternative microglial activation, such as FIZZ‐1, YM‐1, Arginase‐1, and IL‐4 were decreased. These results were confirmed in microglial cultures stimulated with apoptotic conditioned medium from MPP⁺‐treated dopaminergic cells, further demonstrating a role of Nrf2 in tuning balance between classical and alternative microglial activation. This study demonstrates a crucial role of Nrf2 in modulation of microglial dynamics and identifies Nrf2 as molecular target to control microglial function in Parkinson's disease (PD) progression. © 2009 Wiley‐Liss, Inc.