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Diabetes worsens stroke outcome and increases the risk of hemorrhagic transformation (HT) after ischemic stroke, especially with tPA treatment. We previously showed that low dose tPA decreased infarct size and improved functional outcome in both male and female control rats with embolic stroke. In the current study, we hypothesized that low dose tPA will also improve the functional recovery after the embolic stroke in both male and female animals with diabetes. Diabetes was induced in age matched male and female Wistar rats with high fat diet and low dose streptozotocin (30 mg/kg, i.p.). Embolic stroke was induced with middle cerebral artery occlusion. The animals were treated with or without tPA (1 mg/kg, i.v.) at 90 min after surgery. Neurological deficits (composite score and adhesive removal test-ART), infarct size, edema ratio, and HT index were assessed 3 days after surgery. The blood flow has increased in the tPA treated animals in the first 1 to 1.5 hr after treatment. The infarct size and edema was not significantly different in untreated animals, but HT was greater in female diabetic rats. The tPA treatment worsened HT in both genders with no change in infarct size. Decline in ART was worsened with tPA treatment in both sexes. Our data suggest that the low dose tPA after ischemic stroke has detrimental effects on the cerebrovascular recovery and functional outcome in both male and female animals with diabetes.