Oestrogen is a complex hormone whose role as a neuroprotectant in experimental stroke has been published in numerous studies. However, although some clinical studies report a reduction in stroke incidence by oestrogen replacement therapy in postmenopausal women, others have found increased mortality and morbidity after stroke. Diathermy occlusion of the proximal middle cerebral artery (MCAO), one of the most reproducible rodent stroke models, has consequently been employed to investigate physiologic and supraphysiologic doses of 17beta-oestradiol on ischaemic brain damage. Lister Hooded rats were ovariectomised (OVX) and a 21-day release pellet (placebo, 0.025 or 0.25 mg 17beta-oestradiol) implanted in the neck. At 2 weeks after OVX, animals underwent MCAO and were perfusion fixed 24 hours later. Neuronal perikaryal damage was assessed from haematoxylin and eosin-stained sections and in adjacent sections, axonal pathology was assessed with amyloid precursor protein and Neurofilament 200 (NF-200) immunohistochemistry. 17beta-Oestradiol induced a dose-dependent increase in neuronal perikaryal damage, 0.025 and 0.25 mg 17beta-oestradiol increased damage by 20% (P<0.05) and 27.5% (P<0.01) compared with placebo. 17beta-Oestradiol did not influence axonal pathology compared with placebo. Our results suggest that 17beta-oestradiol treatment can exacerbate brain damage in experimental stroke. Thus, further investigation into the role of oestrogen and the mechanisms which mediate its effects in stroke is required.