Oxidative stress and reduced brain glutathione (GSH) levels have been reported in psychiatric illnesses including schizophrenia and bipolar disorder. However the role of GSH in cognitive impairment in the illness remains unclear. Treatment of Sprague-Dawley rats and C57Bl/6 mice with 2-cyclohexene-1-one (CHX) dose-dependently reduced striatal and frontal cortical GSH levels similar to those in schizophrenia. In both species, GSH depletion resulted in disruption of short-term spatial recognition memory in a Y-maze test. In conclusion, GSH depletion induces cognitive impairment, which may be relevant to the role of GSH in psychiatric illnesses.