Aim: The aim of the present study is to investigate the neuroprotective effects of l-Arginine (l-arg) in the seven-day-old rat hypoxia-ischemia model. Materials and methods: L-Arginine (n = 10) or saline (n = 8) was administered intraperitoneally to seven-day-old rats before hypoxia-ischemia. In addition, 18 seven-day-old rats were given l-Arginine (n = 10) or saline (n = 8) after hypoxic-ischemic insult. Neuronal apoptosis was investigated by terminal dUDP-biotin nick end-labeling (TUNEL) following three days of recovery. The ratios of right side numerical density to the sum of right and left sides' numerical densities (right apoptosis index) were calculated for every brain region in rats receiving l-arginine and they were compared with the vehicle groups. Results: Right side apoptosis indexes of the hippocampus (mean +/- SD; 35.0 +/- 16.1) and striatum (41.9 +/- 16.0) were significantly decreased in the l-Arginine post-treatment groups when compared to vehicles (61.0 +/- 17.0 and 62.4 +/- 27.0 respectively) (p < 0.05). There was no significant difference in the right apoptosis indexes of the cortex between l-Arginine post-treated group and the vehicle group. There were also no significant differences between the right side apoptosis indexes of the l-Arginine pretreatment groups and those of the vehicle group in any of the three regions (p > 0.05). Conclusions: It is concluded that neuronal apoptosis due to hypoxic-ischemic injury may likely to be reduced by post-treatment of l-Arginine in the neonatal rat model and l-Arginine provides a new possibility for neuroprotective strategies based on NO production.