Estradiol replacement facilitates kindling from a limbic region, the amygdala. This study determined if estradiol also interacts with kindling from a non-limbic region, the anterior neocortex. Ovariectomized female rats with estradiol replacement required 24 +/- 1.6 trials to kindle and accumulated 434 +/- 28 sec of afterdischarge (AD), significantly less than the 38 +/- 2.2 trials and 840 +/- sec in rats without estradiol. Estradiol replacement did not significantly alter the long series of focal cortical seizures preceding generalized seizures in spite of the early appearance of AD in the contralateral amygdala. Estradiol significantly advanced the onset of generalized seizures compared to rats without estradiol (19 +/- 0.6 versus 24 +/- 1.9 trials). Following secondary seizure generalization, estradiol rats rapidly completed late kindled seizure acquisition. In contrast, late kindling in rats without estradiol was slower as reflected by a 3-fold greater number of AD trials and AD seconds to complete kindling compared to rats with estradiol. One factor in the slower late kindling of rats without estradiol was the instability of generalized seizures which frequently regressed to focal or partial responses. The results provide further experimental evidence for a role for estradiol in catamenial epilepsy and suggest that the process of secondarily generalization of seizures is especially sensitive to estradiol.