Because both brain and its vasculature are potent targets of estrogen, age-related decline in estrogen levels or alterations in estrogen receptors may disrupt the integrity of the blood-brain barrier, leading to increased influx of toxic products. The present study tested the hypothesis that the blood-brain barrier is more permeable in reproductive senescent animals and will respond differently to estrogen replacement as compared with young adult females. Young adult and reproductive senescent rats were ovariectomized and replaced with an estrogen or control pellet. We found a 2- to 4-fold increase in extravasation of dye in the olfactory bulb and hippocampus of reproductive senescent females compared with young adults. Furthermore, estrogen significantly reduced dye extravasation in both olfactory bulb and hippocampus in young adults compared with age-matched counterparts that received a control pellet. However, estrogen replacement increased dye extravasation in the hippocampus of reproductive senescent females compared with age-matched control-pellet replaced animals, whereas dye extravasation was unchanged by estrogen in the olfactory bulb of senescent females. There were no age- and estrogen-related differences in dye accumulation in the pituitary gland, which is a circumventricular organ. These results support the hypothesis that the hormonal decline that marks reproductive senescence leads to increased permeability of the blood-brain barrier, which is further exacerbated by estrogen treatment in specific regions.