Aldose reductase (AR), the first enzyme in the polyol pathway, has been implicated in a wide variety of physiological and pathological functions, such as diabetic vascular and neural complications. It is known that diabetes mellitus can exacerbate brain and retina damage after ischemic injuries. However, the underlying mechanisms are not clear. In the present study, we made use of db/db mice with an AR null mutation (AR(-/-)db/db) to understand better the role of AR in the pathogenesis of brain and retina ischemic injuries under diabetic conditions. Cerebral and retinal ischemia was induced by transient middle cerebral artery occlusion in control and diabetic mice either with or without an AR null mutation. Mice were evaluated for neurological deficits after 30 min of ischemia and 23.5 hr of reperfusion. Our results showed that the diabetic db/db mice had significantly more severe neurological deficit and larger brain infarct size than the nondiabetic mice. Compared with wild-type db/db mice, the AR(-/-)db/db mice had significantly lower neurological scores, smaller brain infarct areas, and less hemispheric brain swelling. Retinal swelling was also significantly decreased in the AR(-/-)db/db mice. Less swelling in the brain and retina of the AR(-/-)db/db mice correlated with less expression of the water channel aquaporin 4. Taken together, these data clearly show that deletion of AR leads to less severe brain and retinal ischemic injuries in the diabetic db/db mouse. The present study indicates that inhibition of AR in diabetics may protect against damage in the brain and retina following ischemic reperfusion injury.