The successful application of thrombolytic therapy to acute myocardial infarction has prompted a reinvestigation of thrombolytic therapy for acute stroke. However, an examination of safety and efficacy of thrombolytic therapy in acute thromboembolic stroke has precluded the entry of patients taking either antiplatelet or anticoagulant therapy. It was therefore of interest, in an established rabbit model of thromboembolic stroke, to examine the use of tissue plasminogen activator therapy in combination with ticlopidine treatment. Following ticlopidine administration (10 mg kg-1, i.v., daily for 5 days), rabbits (n = 7) were embolized by injecting a tin-laden clot into the internal carotid artery with clot placement confirmed by x-ray. Three hours later, t-PA was initiated as a square-wave pulse (6.3 mg kg-1 total dose, given as a 20% bolus, with the remainder administered over 2 h as a continuous infusion). The protocol was continued for a total of 7 h following embolization. Complete clot lysis was demonstrated in 6 of 7 animals. Brain infarct size (triphenyltetrazolium chloride staining) was 36.0 +/- 12.9% hemisphere (mean +/- SEM). Both clot lysis rate and infarct size were very similar to that previously seen following administration of t-PA alone (58% and 31.6 +/- 6.4% hemisphere, respectively) but in marked contrast to previous results seen with intravenous aspirin (no clot lysis). These results suggest that antiplatelet agents used clinically for stroke prophylaxis (aspirin or ticlopidine) may influence the success rate of thrombolysis following initiation of thrombolytic therapy for acute thromboembolic stroke.