Oxytocin (OXT), a nonapeptide hormone of posterior pituitary, reaches the central nervous system from systemic blood circulation with a difficulty because of the blood-brain barrier (BBB). The interest has been expressed in the use of the nasal route for delivery of OXT to the brain directly, exploiting the olfactory pathway. Our previous study has demonstrated that OXT in the central nervous system rather than the blood circulation plays an important role in rat pain modulation. The communication tried to investigate the interaction between the OXT and pain modulation in Chinese patients with headache to understand the OXT effect on human pain modulation. The results showed that (1) intranasal OXT could relieve the human headache in a dose-dependent manner; (2) OXT concentration in both plasma and cerebrospinal fluid (CSF) increased significantly in headache patients in relation with the pain level; and (3) there was a positive relationship between plasma and CSF OXT concentration in headache patients. The data suggested that intranasal OXT, which was delivered to the central nervous system through olfactory region, could treat human headache and OXT might be a potential drug of headache relief by intranasal administration. Copyright © 2013 Elsevier Ltd. All rights reserved.