Agmatine (l-amino-4-guanidinobutane) is an endogenous polycationic amine synthesized by the decarboxylation of arginine by the enzyme arginine decarboxylase and hydrolysed by agmatinase. Agmatine has been quantified in nearly all organs including brain. It has been proposed to act as a novel neuromodulator in the mammalian brain. Previous studies have shown that endogenous agmatine interacts with a number of receptor subtypes such as, imidazoline, 2-adrenergic and N-methyl-D-aspartate. It also blocks other ligand-gated cationic channels, including nicotinic receptors, and inhibits all three isoforms of nitric oxide synthase. Although there are papers showing that agmatine may have a modulator role in learning and memory, the question of whether it is able to reverse impaired learning and memory still remains. This study was planned to investigate the effect of agmatine on cognitive functions and oxidative damage following chronic unpredictable mild stress (CUMS). Rats were allocated to the following study groups: animals not exposed to CUMS (control group, n=12), animals exposed to CUMS for 5 weeks (CUMS group, n=12), animals exposed to CUMS and treated with agmatine (CUMS+Agmatine Group, n=12). The control and CUMS groups were injected with saline and the CUMS+Agmatine group was injected with agmatine 40 mg/kg, i.p. daily throughout the experiment. CUMS was applied according a previous study with a minor modification. Brieşy, the CUMS and CUMS+Agmatine groups were subjected to different types of stressors: restraints for 4 h, cage tilting for 24 h, wet bedding for 24 h, swimming in 40C cold water for 5 min, swimming in 45 C hot water for 5 min, pairing with another stressed animal for 48 h, level shaking for 10 min, nip tail for 1 min, and inversion of the light/dark cycle for 24 h. These nine stressors were randomly applied for 5 weeks. The rats received one of these stressors per day and the same stressor was not applied continuously for 2 days so that animals could not predict the occurence of stimulation. After 5 weeks, animals were tested in the passive avoidance (PA) and Morris's water maze (MWM) tasks to evaluate learning and memory functions. At the end of the experiment, the brains of the rats were either removed freshly for malondialdehyde (MDA), glutathione (GSH) levels and myeloperoxidase (MPO) activity or removed with 4% paraformaldehyde perfusion for c-fos, glial fibrillary acidic protein (GFAP) and brain-derived neurotrophic factor (BDNF) determination immunohistochemically in cortex and hippocampus. There was a significant defect in cognitive functions of the CUMS group whereas agmatine treatment significantly reversed this effect both in the PA and MWM tests. A decrease in GSH and an increase in MDA and MPO levels in the CUMS group were significantly inhibited with agmatine treatment, which were considered markers of oxidative damage. In the immunohistochemical experiments, it was found that c-fos and GFAP were overexpressed and BDNF was decreased in the CUMS group whereas data for the agmatine treatment group were similar to those of the control group. The findings of the current study clearly showed beneficial effects of agmatine on cognitive impairment and oxidative damage in CUMS.