We investigated the efficacy and safety of intrapleural instillation of recombinant tissue plasminogen activator (Alteplase) in 120 patients with complicated pleural effusion (CPE) or empyema. These 120 patients had failed simple chest tube placement and conventional medical treatment. The patients included 52 with empyema, 41 with CPE, 10 with hemothorax, and 17 with complicated malignant pleural effusions. A total of 345 doses of Alteplase were instilled intrapleurally in these patients, with doses ranging from 10 to 100 mg daily. Most patients required 3 to 4 doses of alteplase. After Alteplase therapy, complete resolution of CPE/empyema occurred in 102 patients (85%), partial resolution in 10 patients (8%), and failure to respond in 8 patients (7%). All patients who failed to respond to Alteplase treatment had either chronic empyema or empyema associated with lung abscesses. Adverse effects of Alteplase therapy were chest pain in 7 patients (6%) and bleeding at the chest tube site in 2 patients (2%).