Although several studies have examined the effects of estrogen replacement therapy (ERT) on neural activity associated with tasks of learning and memory, no study has examined such effects on a sustained attention task. This study examined the effect of low-dose estrogen replacement therapy on hemodynamic activity elicited by a visual three-stimulus oddball task recorded using event-related functional magnetic resonance imaging (fMRI). Participants included 16 women between the ages of 73 and 84 who were part of a randomized controlled double-blind study to evaluate the effect of an ultralow dose micronized estradiol on bone. No significant differences in behavioral performance were found with ERT. However, there was evidence that ERT group participants had both reductions and increases in the amplitude of hemodynamic response in a variety of subcortical and cortical brain regions. These included regions involved in perception and attention such as the occipital and parietal lobes, motor cortex, anterior cingulate and prefrontal cortex. These findings suggest that estrogen may facilitate the efficiency of brain function during the performance of sustained attention tasks in post-menopausal elderly women.