Murine mature splenic DC with elevated intracellular glutathione, pretreated with IL‐18, strikingly augmented the production of IFN‐γ in response to IL‐12, whereas intracellular glutathione deprivation ablated this effect of IL‐18. Likewise, macrophages with elevated intracellular glutathione augmented IFN‐γ production upon LPS or IL‐12+IL‐18 stimulation, whereas macrophages withreduced intracellular glutathione showed the reciprocal response. Under hypoxia, macrophages displayed a functional phenotype with decreased intracellular glutathione, i.e. decreased NO and IL‐12, and elevated IL‐10 production. However, mature DC and macrophages produced an elevated amount of IFN‐γ under hypoxia. Taken together, our results suggest that the intracellular redox status of DC and macrophages may play a pivotal role in local innate immunity, depending on local oxygen tension.