Our previous research has shown that electrolytic lesions of the posterior septum result in dramatic, antianxiety effects in two different animal models of anxiolytic drug action, i.e., a selective increase in open-arm activity in the elevated plus-maze test, and a selective abolition of defensive burying in the shock-probe burying test. Although these results suggest that posterior regions of the septum play an important role in the expression of anxiety in these tests, it is unclear whether destruction of septal nuclei themselves mediated these effects, since electrolytic lesions also destroy fibers of passage. Accordingly, in the present experiments, the anxiolytic effects of electrolytic lesions of the septum were compared to those of excitotoxic lesions, which preferentially destroy cell bodies, leaving fibers of passage intact. In the first experiment, both electrolytic and kainic acid lesions of the posterior septum produced complete anxiolytic effects in the elevated plus-maze (an increase in the percentage of open-arm entries and percentage of time in open arms), and partial anxiolytic effects in the shock-probe test (an increase in contact-induced probe shocks), compared to sham-lesioned controls. These antianxiety effects could not be attributed to an increase in general activity, or a decrease in reactivity to shock. In the second experiment, excitotoxic lesions of the posterior septum were produced by a more selective agent, quisqualic acid. Quisqualic acid, like electrolytic lesions, produced clear, anxiolytic effects in both the plus-maze and the shock-probe tests, compared to sham-lesioned control. Taken together, these results strongly suggest that cells originating in posterior regions of the septum mediate anxiety-related responses.