Leptin is an adipocyte-secreted hormone that centrally regulates weight control via targeting the leptin receptor in the central nervous system. Recently, the leptin receptor has also been detected in peripheral systems including immune tissues, suggesting that leptin may play an important role in the regulation of immune function. It has been shown that leptin modulates functions of T lymphocytes, B lymphocytes, and monocytes/macrophage. However, the effect of leptin on NK cells remains unknown. In the present paper, we observed that percentage of NK cells and total amount of NK cells in the liver, spleen, lung, and peripheral blood were declined in leptin receptor deficient mice (db/db B6 mice), indicating that NK cell development was vigorously influenced by leptin receptor deficiency. Both basal and poly I:C-stimulated NK cell activation (CD69 surface marker expression) were retarded in db/db mice. In addition, leptin treatment increased the basal or synergistically enhanced IL-15- and poly I:C-induced specific lysis of splenocytes in normal littermates but not in db/db mice. Taken together, these findings suggest that leptin plays an important role in NK cell development and activation.