Rats submitted to middle cerebral artery (MCA) clot embolism were treated with tissue plasminogen activator (TPA) 1.5 and 3.5 h post-occlusion. Reperfusion patterns were monitored by measuring cortical laser-Doppler flow; the direct current potential was measured to detect peri-infarct depolarizations (PID), a known mechanism of ischemic injury. TPA treatment induced reperfusion in 58% of treated animals that was delayed by 41 +/- 7 min (mean +/- s.e.m.) from treatment onset. The probability of reperfusion did not differ significantly between the two treatment groups. TPA treatment led to a 3-fold reduced frequency of PID if administered early or if successful reperfusion was observed (each p < 0.001). Early thrombolysis inhibits, but does not block, PID as an important mechanism of ischemic injury in embolic stroke.