Purpose: To assess the feasibility and effectiveness of intrapleural recombinant tissue-type plasminogen activator (r-tPA) in the treatment of loculated parapneumonic effusions (PPEs). Materials and Methods: A single-arm prospective study of 25 consecutive patients with loculated PPEs was analyzed. All patients received 6-mg doses of intrapleural r-tPA on a defined schedule via a thoracostomy tube. The volume of output from the tubes was recorded and analysis of the fluid composition performed. Follow-up was both clinical and radiographic, with all patients undergoing pre- and postprocedural computed tomography. Results: Eighteen of the 25 patients (72%) required no additional intervention and had a complete clinical and radiographic response with the fibrinolytic therapy. Seven patients (28%) were treated with video-assisted thoracoscopic surgery, but no patient required thoracotomy for total decortication. There were no hemorrhagic complications. Conclusions: Intrapleural r-tPA is effective in the treatment of loculated PPEs. It can be performed safely and in some patients may avoid the need for additional surgical intervention.