The effects of iontophoretically applied 17 alpha- and 17 beta-estradiol on the spontaneous firing of, and actions of purines (adenosine, adenosine 5'-N-ethylcarboxamide) on, neurons in the rat cerebral cortex have been determined. Both steroids, applied as acetate, sulphate or hemisuccinate esters, depressed the spontaneous firing of approximately half of the neurons tested. 17 beta-Estradiol potentiated the inhibitory actions of adenosine on some neurons (26%) and antagonized the effects of adenosine on others (42%). 17 beta-Estradiol antagonized the inhibitory actions of adenosine 5'-N-ethylcarboxamide on 76% of the neurons tested, but did not enhance the actions of this uptake resistant adenosine analog. 17 alpha-Estradiol potentiated the actions of adenosine and adenosine 5'-N-ethylcarboxamide but failed to antagonize either purine. It is suggested that the potentiating effects of both stereoisomers on adenosine are a result of their ability to block adenosine uptake and that 17 beta-estradiol is also able to antagonize the actions of these purines. Antagonism of the effects of endogenously released adenosine may account for the excitant actions of 17 beta-estradiol on the central nervous system.