Neuropeptide Y (NPY) was shown to modulate anxiety- and depression-related behaviors in various animal models. Previous studies demonstrated that NPY Y₂ receptor knockout (KO) mice display an anxiolytic- and antidepressant-like phenotype compared with control animals. However, the long-term effect of the deletion of this receptor in aged animals is unknown. Thus, anxiety- and depression-related behaviors were investigated in 2-yr-old NPY Y₂ KO mice. Aged NPY Y₂ KO mice display an anxiolytic-like profile as assessed in the elevated plus-maze and open field, providing further support for a role for Y₂ receptors in anxiety-related behaviors. Furthermore, aged NPY Y₂ KO mice have significantly lower immobility scores in the forced swim test; supproting the role for this receptor in antidepressand-like behaviors. These data provide further evidence that modulators of the NPY Y₂ receptor subtype are drug targets for the treatment of anxiety and mood disorders in human subjects.