Brain mononuclear phagocyte (perivascular macrophage and microglia, MG) inflammatory neurotoxins play a principal role in the pathogenesis of Parkinson's disease; chief among these are reactive oxygen species (ROS). We posit that aggregated, misfolded and oxidized alpha-synuclein (a major constituent of Lewy bodies), released or secreted from dying dopaminergic neurons, induces microglial ROS production that is regulated by ion channels and as such affects disease progression. To address this hypothesis, we performed patch clamp recordings of outward ionic currents in murine microglia and characterized their links to ROS production during alpha-synuclein stimulation. Aggregated nitrated alpha-synuclein induced ROS production in a dose-dependent manner that was inhibited by voltage-gated potassium current blockade, and to a more limited degree, by chloride current blockade. Interestingly, ROS produced in MG primed with tumor necrosis factor alpha and activated with phorbol myristate acetate was attenuated by voltage-gated potassium current blockade and more completely by chloride current blockade. In contrast, amyloid beta or cell membrane extract failed to induce microglial ROS production. Similar results were obtained using bone marrow-derived macrophages. The association of ROS production with specific plasma membrane ion currents provides a link between regulation of microglial ion transport and oxygen free radical production. Understanding these linkages may lead to novel therapeutics for Parkinson's disease where modulation of redox-related stress may slow disease progression.