Recombinant tissue-plasminogen activator (t-PA) increases brain injury after focal ischemias leading to overt tissue infarcts. The question arose, whether t-PA may also be detrimental after mild ischemias. To clarify this issue, we submitted mice to 30 min intraluminal thread occlusions and administered normal saline or t-PA (10 mg/kg, i.v.) after reperfusion onset. Thread occlusions resulted in reproducible ischemias, followed by hyperperfusion reactions immediately after thread withdrawal. Post-ischemic LDF did not differ between saline- and t-PA-treated animals. In contrast to earlier studies, where t-PA exacerbated injury, t-PA treatment did not increase, but attenuated disseminate neuronal death in the striatum, as shown by cresyl violet, TUNEL and activated caspase-3 staining 1 and 3 days after the ischemic event (p < 0.05). Our data argue against major detrimental actions of t-PA after mild focal ischemia.