OBJECTIVE Timely intravenous administration of recombinant tissue-type plasminogen activator (alteplase, rTPA) to patients with evolving ischemic stroke improves neurological outcome. The present study was designed to compare the effects of rTPA and recombinant staphylokinase (Sak), a highly fibrin-specific thrombolytic agent, in an experimental model of rabbit embolic stroke. METHODS Groups of 5 to 12 rabbits were given intravenous saline or heparin and aspirin with, in addition, either Sak (1 or 2 mg/kg infused over 30 minutes or 2 mg/kg injected over 1 minute) or rTPA (3 or 6 mg/kg infused over 30 minutes or 6 mg/kg injected over 1 minute). Infusions were started 15 minutes after selective injection of standardized 125I-fibrin labeled rabbit plasma clots into the internal carotid artery. RESULTS Mean clot lysis over 60 minutes increased from 3.8% after saline to between 27% and 44% after Sak regimens (P = .0001 versus control) and to between 15% and 34% after rTPA regimens (P = .0001). Median volume of the ischemic lesion at 5 hours decreased from 190 mm3 after saline to between 11 and 17 mm3 after Sak (P = .02) and to between 0.5 to 54 mm3 after rTPA (P = .04). Mean neurological impairment at 5 hours (on a scale of 0 to 3) decreased from 2.3 after saline to between 1.3 to 1.6 after Sak (P = .003) and to between 1.1 to 1.9 after rTPA (P = .02). At the highest doses used, fibrinogen depletion was marginal with Sak but total with rTPA. Marked prolongation of car puncture and cuticle bleeding times was only observed after bolus administration of rTPA. CONCLUSIONS In the present rabbit model of embolic stroke, Sak was significantly more fibrin-specific than rTPA and at least as effective in lysing arterial emboli and limiting ischemia and neurological impairment.