Urokinase (UK), a potent thrombolytic agent, was tested in a rabbit model for safety and efficacy in lysing intracranial hematomas. Intracerebral-intraventricular (IC-IV) hematomas were created by stereotaxically injecting 0.2 ml of clotted human blood into the frontal lobe and lateral ventricle of a total of 57 anesthetized adult New Zealand White rabbits (weighing 1.6 to 2.5 kg). Control animals received 0.2 ml of normal saline injected into the clot, and the experimental group received an equal volume of UK solution (50,000 units/ml) immediately after the clot injection. Some animals were sacrificed at 3 hours and others at 24 hours postinjection. At 3 hours, clot lysis had been achieved in nine (90%) of 10 UK-treated animals as compared to one (14%) of seven controls. By 24 hours, clots had been lysed in 10 (83%) of 12 UK-treated animals and in two (33%) of six controls. Overall, clot lysis was demonstrated in 19 (86%) of the 22 UK-treated animals and in only three (23%) of the 13 controls (p less than 0.001). There was no significant difference in results between these animals and a further set of 22 rabbits that were treated with UK or saline 24 hours after clot injection. There was no histological evidence of damage or inflammation noted on careful light microscopic examination of three to five sections from each brain, although findings consistent with encephalitozoonosis, an incidental protozoan infestation, were encountered in four animals. These studies suggest that UK may be safely and effectively employed for the lysis of intracranial hematomas in this animal model, and that a delay in therapy of up to 24 hours does not significantly compromise its efficacy.