Previous studies have observed that the gaseous neurotransmitter nitric oxide (NO) and the neuronal NO synthase (NOS1) are involved in the pathogenesis of depression. The chronic unpredictable stress (CUS) rats model is one of the important models to study the pathogenesis of depression. It remained, however, unclear whether the CUS model may show similar molecular changes, such as alterations in the NOS1-NO system, to those in the depressive patients. In the present study, we compared the changes in the plasma levels of NO and the NOS activity in the brain of rats exposed to CUS with those in medicine-naïve major depressive disorder (MDD) patients, with the purpose of making clear whether the CUS rat model could be used for studying the NOS-NO system in MDD. It was observed that changes in plasma and hypothalamic NOS-NO systems of CUS rats and of the MDD patients are highly similar. The CUS rat model may thus be helpful for the investigation on the alterations in NO system in MDD.