Aims: Uncoupling protein 2 (UCP2) is a mitochondrial protein that reduces oxidative stress and has a protective function in chronic inflammatory diseases such as multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus. UCP2 is strongly expressed in areas implicated in the central regulation of stress and anxiety. Therefore, we compared the neuroendocrine regulation of stress responses, immunity and behavior in UCP2-deficient and wildtype C57BL/6J mice under psychological stress. Main methods: Stress was induced by social disruption (SDR) and anxiety-like behavior was examined using the elevated plus-maze (EPM). Serum corticosterone was determined by radioimmunoassay and brain neurotransmitter concentrations were analyzed by HPLC of whole brain homogenates. T cell activation and tumor necrosis factor (TNF)-α production of mitogen-activated splenocytes were determined in vitro by flow cytometry staining of CD25, CD69 and CD71 on CD4 cells, and ELISA, respectively. The influence of corticosterone on UCP2 expression of splenocytes was analyzed by Western blot. Key findings: At baseline, UCP2-deficient mice were significantly more anxious in the EPM than wildtype mice, and this phenotype was exacerbated after SDR stress. The corticosterone response after SDR + EPM was reduced in UCP2-deficient mice compared to wildtype mice. Corticosterone in turn downregulates UCP2 expression in splenocyte cultures of wildtype mice at physiological concentrations. Dopaminergic and serotonergic turnovers were increased in UCP2-deficient mice after SDR + EPM. While T-helper cell activation-marker expression was reduced, TNF-α production was increased in UCP2-deficient mice after SDR + EPM. Significance: Our study shows that UCP2 is involved in anxiety-like behavior and modulates neuroendocrine and immune responses after stress.