Although a variety of potential sources for reactive oxygen species (ROS) exist in the CNS, brain macrophages, i.e., the microglia, generate large quantities of these reactive species, particularly in response to injury or inflammatory signals. In order to understand how microglia contribute to changes in oxidative status of the CNS and how this might related to disease states, such as Alzheimer disease (AD), we have examined the regulation of superoxide anion and nitric oxide production from rodent and human microglia. Our results indicate that microglia from all species we have studied release superoxide anion, but produce significantly different amounts in response to the same activating agents. Species differences are also found in the ability to generate nitric oxide (NO). In particular, mouse microglia generate large quantities of NO when stimulated, but human and hamster microglia do not produce measurable amounts under the same stimulation conditions. These species differences are important to consider when modeling human disease processes from rodent studies.