Interdependence between estradiol and insulin-like growth factor-I has been documented for different neural events, including neuronal differentiation, synaptic plasticity, neuroendocrine regulation and neuroprotection. In the present study we have assessed whether both factors interact in the regulation of neurogenesis in the adult rat dentate gyrus. Wistar albino female rats were bilaterally ovariectomized and treated with estradiol, insulin-like growth factor-I and/or the estrogen receptor antagonist ICI 182,780. Estradiol was administered in a subcutaneous silastic capsule. Insulin-like growth factor-I and ICI 182,780 were delivered in the lateral cerebral ventricle. Animals received six daily injections of 5-bromo-2-deoxyuridine and were killed 24 h after the last injection. The total number of 5-bromo-2-deoxyuridine-positive neurons was significantly increased in animals treated with insulin-like growth factor-I, compared with rats treated with vehicles, while rats treated with both insulin-like growth factor-I and estradiol showed a higher number of 5-bromo-2-deoxyuridine-positive neurons than rats treated with insulin-like growth factor-I or estradiol alone. The antiestrogen ICI 182,780 blocked the effect of insulin-like growth factor-I on the number of 5-bromo-2-deoxyuridine neurons with independence of whether the animals were treated or not with estradiol. These findings suggest that estrogen receptors are involved in the induction of adult neurogenesis by insulin-like growth factor-I in the dentate gyrus, and that estradiol and insulin-like growth factor-I have a cooperative interaction to promote neurogenesis. The interaction between insulin-like growth factor-I and estradiol may participate in changes in the rate of neurogenesis during different endocrine and physiological conditions, and may be related to the decline in neurogenesis with ageing.