Recent research in rodents suggests that extended and chronic hormone therapy can exacerbate memory impairments and irreversibly damage cells. However, aerobic fitness regimens have been shown to spare brain tissue and cognitive function. In addition, interactions between estrogen treatment and exercise have been reported in rodents. However, whether aerobic fitness and hormone treatments show interactive effects on human brain tissue and cognition has yet to be determined. Here we report two unique and important results: (a) HRT treatment up to 10 years in duration spares gray matter in prefrontal cortex and is associated with better performance on measures of executive function, whereas HRT treatment beyond 10 years in duration increases the degree of prefrontal deterioration and amplifies the decline on measures of executive functioning (b) higher fitness levels augment the effects of shorter durations of hormone treatment and ameliorate the declines associated with prolonged hormone treatment.