Background: Kisspeptins are recognized as important stimulators of gonadotropin-releasing hormone (GnRH) and gonadotropin secretion. In sheep, the nonbreeding (anestrous) period is characterized by reduced Kiss1 mRNA expression in the hypothalamus. The aim of the present study was to determine whether the response to kisspeptin treatment varies between the breeding and nonbreeding seasons. Methods: Corriedale ewes were treated intravenously with murine kisspeptin-10 (submaximal dose: 20 mug or maximal dose: 250 mug) or GnRH (250 ng) during either the anestrous period or during the breeding season at the luteal, mid-follicular, or late-follicular phase of the estrous cycle. Results: Kisspeptin treatment increased the concentration of luteinizing hormone (LH) in all animals. We found the LH response to kisspeptin (20 mug) was greater in ewes during the anestrous period, being 4-fold that seen during the luteal phase of the estrous cycle. Within the breeding season, kisspeptin (20 mug) was most effective during the late-follicular phase of the estrous cycle. Kisspeptin treatment (both 20 and 250 mug) had no effect on plasma levels of growth hormone, prolactin or cortisol. The variable effect of kisspeptin (20 mug) on LH secretion appeared to mirror that of GnRH treatment indicating that the effect may be mediated by a change in the pituitary response to GnRH. Conclusion: We conclude that the gonadotropic response to kisspeptin depends upon the reproductive status of the female.