In infective endocarditis vegetations are stabilized by fibrin. To learn if fibrin digestion would be therapeutic, experimental endocarditis was induced in rabbits by inoculation with a platelet-aggregating strain (Agg+) of Streptococcus sanguis and treated with recombinant tissue plasminogen activator (rt-PA), α-PA with penicillin, or penicillin alone. Control rabbits were inoculated with saline. All treatments of Agg+ endocarditis reduced the mass of valvular vegetations and clinical signs of endocarditis, including the frequency of left axis deviation and heart ischemia. rt-PA with penicillin was more effective than penicillin or rt-PA alone, reducing the mass of vegetations and clinical signs to that of saline controls. Within 50 min, rt-PA cleared 5-fold more 111Indium-labelled platelets from the heart than untreated rabbits and 1.4-fold more after 3 days. Combined with penicillin, thrombolytic therapy for human endocarditis should be reconsidered.