Background: Reports assessing the neuroprotective role of nonselective NO synthase (NOS) inhibitors following cerebral ischemia/reperfusion are contradictory (1-2). Aims: To examine the potential benefits of N-nitro-L-arginine-methylester (L-NAME) on rats subjected to transient focal cerebral ischemia/reperfusion. Materials and methods: The study involved three groups of males adult Wister rat each consist of 10: a control group operated at the neck region without occlusion of left common carotid artery (CCA), a placebo group infused with 0.9% normal saline intraperitoneally 15 minutes prior to left cerebral ischemia/reperfusion induced by transient (30 minutes) left CCA occlusion and a test group infused with L-NAME intraperitoneally 15 minutes prior left cerebral ischemia/reperfusion (3). Anesthesia was induced by ether inhalation and maintained by thiopental sodium (2.5mg/kg). Malondialdehyde (MDA), NO metabolites and total antioxidant capacity (TAC) in serum and the affected cerebral hemisphere were measured. Neurobehavioral deficits were evaluated. Results: The neurological deficit of both placebo and test groups were significantly lower compared to the control group. The test group showed a significant improvement in neurological deficit compared to the placebo group (P <0.001).The placebo group demonstrated a significant increase in the serum levels of both MDA and NO (14.88±1.14 nmol/mL, 42.03±4.56 μmol/L respectively) compared to the control group (5.43±0.44 nmol/mL, 17.84±0.7 μmol/L respectively, P <0.001). Values are means ± S.E.M., compared by ANOVA. Alternatively, the test group showed significant decrease in serum level of MDA and NO (7.18±0.13, 18.44±0.51μmol/L respectively, P <0.001) compared to the placebo group. The serum level of TAC in the placebo group (1.21±0.17 mM/L) was significantly lower compared to the control group (2.52±0.06 mM/L, P <0.001) but not the test group (2.53±0.067mM/L). L-NAME pretreatment resulted in significant higher serum level of TAC compare to placebo group (P <0.001).The brain tissue levels of MDA and NO of the placebo group (8.56±0.7, 8.88±0.57 nmol/mg protein) was significantly higher than the control group (3.24±0.22, 3.48±0.22 nmol/mg protein, P <0.001). The test group showed a significant decrease in tissue level of MDA and NO (3.18±0.1, 4.47±0.4 nmol/mg protein, P <0.001) compared to the placebo group. Administration of L-NAME prior to ischemia result in significant increase of brain TAC level compare to placebo (0.07±0.009 vs 0.02±0.004 mmol/mg protein P < 0.001). Conclusions: L-NAME pretreatment for rats undergoing cerebral ischemia/reperfusion significantly improve neurological deficit through reducing oxidative stress biomarkers in the affected cerebral hemisphere.