Introduction: It has been suggested that histamine have modulatory influence on anxiety-related behaviors both in human and animals. lateral septum (LS) may also be an important brain site in modulation of fear and anxiety.Methods: In the present study, the effects of histaminergic agents on anxiety-related behaviors in the rats, using elevated-plus maze TEST has been investigated, and anxiety parameters such as open arm time (OAT), open arm entries (OAE) and locomotor activity (LOC) have been avaluated.Results: Intra-LS administration of histamine (0.1, 0.5, 1μg/rat), decreased %OAE and %OAT but not locomotor activity. Showing an anxiogenic response. Intra-LS microinjections of pyrilamine (a H1 receptor antagonist) or ranitidine (a H2 receptor antagonist) (5, 10, 20μg/rat) alone had no effect on mentioned parameters. Pretreatment of animals with either pyrilamine or ranitidine in mentioned doses, revers anxiogenic response of histamine (1 μg/rat).Conclusion: Our results showed that histamine may modulate anxiety-like behaviors via H1 and H2 receptors in the lateral septum on the rats.