We studied whether intraperitoneal fibrinolysis using recombinant tissue plasminogen activator (t-PA) could prevent abscess formation in the rat model of intra-abdominal infection caused by fibrin clots. Single-dose administration of t-PA at concentrations greater than 0.005 mg/mL at surgery or delivered by open lavage within 1 h of surgery completely obviated abscess formation induced by Bacteroides fragilis-infected clots without altering mortality (approximately 0.6%). With mixed Escherichia coli-B. fragilis clots, t-PA increased the mortality rate from the control level of 43.8% to 81.3% but prevented abscesses in survivors. This increased mortality rate was probably due to an acute E. coli bacteremia. Antibiotics plus t-PA prevented both mortality and abscess formation. Intraperitoneal fibrinolysis may be a useful adjunct to antibiotics and appropriate surgery in the management of intra-abdominal infection.