The time required for the effective clearance of pleural adhesions/organization after intrapleural fibrinolytic therapy (IPFT) is unknown. Chest ultrasonography and computed tomography (CT) were used to assess the efficacy of IPFT in a rabbit model of tetracycline-induced pleural injury, treated with single-chain (sc) urokinase plasminogen activators (scuPAs) or tissue PAs (sctPA). IPFT with sctPA (0.145 mg/kg; n ϭ 10) and scuPA (0.5 mg/kg; n ϭ 12) was monitored by serial ultrasonography alone (n ϭ 12) or alongside CT scanning (n ϭ 10). IPFT efficacy was assessed with gross lung injury scores (GLIS) and ultrasonography scores (USS). Pleural fluids withdrawn at 0 -240 min and 24 h after IPFT were assayed for PA and fibrinolytic activities, ␣-macroglobulin/ fibrinolysin complexes, and active PA inhibitor 1 (PAI-1). scuPA and sctPA generated comparable steady-state fibrinolytic activities by 20 min. PA activity in the scuPA group decreased slower than the sctPA group (k obs ϭ 0.016 and 0.042 min Ϫ1 ). Significant amounts of bioactive uPA/␣-macroglobulin (but not tPA; P Ͻ 0.05) complexes accumulated at 0 -40 min after IPFT. Despite the differences in intrapleural processing, IPFT with either fibrinolysin was effective (GLIS Յ 10) in animals imaged with ultrasonography only. USS correlated well with postmortem GLIS (r 2 ϭ 0.85) and confirmed relatively slow intrapleural fibrinolysis after IPFT, which coincided with effective clearance of adhesions/organization at 4 -8 h. CT scanning was associated with less effective (GLIS Ͼ 10) IPFT and higher levels of active PAI-1 at 24 h following therapy. We concluded that intrapleural fibrinolysis in tetracycline-induced pleural injury in rabbits is relatively slow (4 -8 h). In CT-scanned animals, elevated PAI-1 activity (possibly radiation induced) reduced the efficacy of IPFT, buttressing the major impact of active PAI-1 on IPFT outcomes. fibrinolytic therapy; fibrinolysis; plasminogen activator inhibitor 1; pleural injury; urokinase; tissue plasminogen activator INTRAPLEURAL FIBRINOLYTIC THERAPY (IPFT) activates the endogenous fibrinolytic system, resolving intrapleural adhesions and complex fibrinous deposits that sequester pockets of inflammation loculations, thus improving drainage and clinical outcome, in part by decreasing surgical interventions (10). There are multiple reports of successful (88 -100% efficacy) IPFT in adult (1,7,8,16,17,29,42,47,48,66,67,72) and in pediatric (2,3,6,11,20,40,41,58,59,61,63,67) patients with empyema although outcomes in adult patients are inconsistent in these trials. Thus IPFT represents a less invasive and costly alternative to video-assisted thoracic surgery or other surgical interventions, which demonstrate comparable efficacy (16,44,45,58,60,71) in pediatric practice. IPFT also represents a preferred choice in high-risk (1, 22) and otherwise inoperable patients (10,43,49,56,57,69) or those with empyema/ loculation who refuse surgery. The reasons for the inconsistent results of IPFT in adult patients remain unclear but likely reflect...