BACKGROUND: Social stress leads to oxidative stress in the central nervous system, contributing to the development of mental disorders. Loss of parvalbumin in interneurons is an important feature of these diseases. We studied the role of the superoxide-producing nicotinamide adenosine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) in rats exposed to social isolation. METHODS: Male rats were kept for 7 weeks in group or in social isolation (n = 6-10 per group). Behavioral tests, immunohistochemistry, and analysis of NOX2 expression were performed at the end of social isolation. Apocynin was given in the drinking water (5 mg/kg/day). RESULTS: NOX2 was below detection level in the brains of control animals, whereas it was highly expressed in isolated rats, particularly in nucleus accumbens and prefrontal cortex. Indirect markers of oxidative stress (oxidized nucleic acid 8-hydroxy-2'-deoxyguanosine, redox-sensitive transcription factor c-fos, and hypoxia-inducible factor-1alpha) were increased after social isolation in brain areas with high NOX2 expression. An increase in immunoreactive microglia suggested that oxidative stress could be in part due to NOX2 activation in microglia. In response to social isolation, rats showed increased locomotor activity, decreased discrimination, signs of oxidative stress in neurons, and loss of parvalbumin-immunoreactivity. Treatment of isolated rats with the antioxidant/NOX inhibitor apocynin prevented the behavioral and histopathological alterations induced by social isolation. CONCLUSIONS: Our data suggest that NOX2-derived oxidative stress is involved in loss of parvalbumin immunoreactivity and development of behavioral alterations after social isolation. These results provide a molecular mechanism for the coupling between social stress and brain oxidative stress, as well as potential new therapeutic avenues.