Orexins/hypocretins are novel neuropeptides originally discovered in neurons in the lateral hypothalamus and are effective in a wide variety of physiological functions such as food intake, sleep/awake cycle and neuroendocrinological response. The aim of this study was to investigate the role of endogenous orexin-A in the inflammatory response. Male Wistar albino rats were divided randomly into three groups, namely saline, carrageenan and carrageenan+SB-334867. The orexin type 1 receptor (OX1R) antagonist SB-334867 was administered to rats to block the effect of orexin-A through OX1R. The carrageenan (1%) was injected into the dorsal air pouches of the rats to induce an inflammatory reaction. Plasma orexin-A level increased significantly due to carrageenan-induced inflammation. The inflammation index, the chemotactic activity of exudate cells and the concentration of pro-inflammatory mediators in exudate increased in response to carrageenan injection. The inflammation index and TNF-α concentration decreased significantly in the group treated with SB-334867 compared to the carrageenan group. OX1R antagonist did not alter the production of PGE2 and NO, the expression of COX-2 and iNOS and the activities of chemotaxis and phagocytosis of exudate cells. These results indicate that orexin-A is involved in inflammation and that the inflammatory effect of orexin-A is independent of NO and PGE2.