To test the efficacy of intrapleural fibrinolytic therapy in patients with loculated pleural effusions, we conducted an open, prospective, and multicenter trial among five hospitals in Mexico. We enrolled patients with hemothorax or empyema, clotted and/or loculated, that was not resolved through conventional pleural drainage with chest tube and antibiotics in patients with empyema. All patients received repeated doses of 250,000 IU of streptokinase through chest tube. Effectiveness criteria were before and after intrapleural streptokinase (IPSK) drainage, and poststreptokinase radiographic and respiratory function test improvement. Forty-eight patients were studied; there were 30 patients with empyemas, 14 with hemothorax, and 4 patients with malignant pleural effusions without lung trapping. Successful fibrinolysis was obtained in 44 patients, with complete resolution of the pleural collection and adequate radiologic and spirometric improvement. In three of four patients with multiloculated malignant hemothorax with high-yielding pleural drainage, IPSK allowed successful lysis of loci and an adequate pleurodesis was achieved. Only four patients required surgical treatment. The overall success rate in our series was 92%, similar to previous reports. The results in this first prospective and multicentric trial suggest that intrapleural fibrinolysis is an effective and safe adjunctive treatment in patients with heterogeneous pleural coagulated and loculated collections to restore the pulmonary function assessed by respiratory function tests and can obviate surgery in most cases.