Purposes: An anti-allergic and analgesic drug, "an extract derived from the inflamed cutaneous tissue of rabbits inoculated with vaccinia virus (ERV)", has been used in medical practice in Japan and some other countries. We examined the effect of ERV, prior to induction of ischemia, on the development of cerebral infarction, on learning and memory, or on brain-derived neurotrophic factor (BDNF) levels in C57BL/6J mice. Methods: Following oral administration of ERV (the same in humans: x 1) or vehicle, daily for three consecutive weeks, temporary focal ischemia was induced by the three vessel occlusion technique. In the other group of animals, after daily ERV (Low: x 1; Med: x 3, or High dose: x 9) or vehicle administration for three weeks, we performed a quantitative assessment of spatial learning or intracerebral BDNF levels. Results: The volumes of infarcted lesions, brain edema and the extent of the neurological deficits were significantly reduced in the ERV-treated group. ERV treatment also enhanced spatial learning, accompanied by upregulated BDNF in the cortex. Conclusions: Daily oral intake of ERV, at a clinically relevant dose, protects the brain from ischemic stroke, and also enhances the learning function in normal mice. As millions of people are currently taking the drug safely, and have been for many years in some cases, there is a need to test the inhibitory actions of the drug on progressive dementia encountered in humans with recurrent ischemic attacks or Alzheimer's disease. (C) 2015 Elsevier B.V. All rights reserved.