The purpose of this study was to assess the value of intrapleural urokinase (UK) instillations in enhancing tube drainage of loculated, complex pleural effusions. Tube thoracostomy has variable success in the treatment of complex pleural effusions, with limitations because of viscous fluid, improper tube position or kinking, and, most importantly, loculation. In the past, intrapleural administration of streptokinase has been used to lyse locules. In this study, eight patients with nine loculated pleural processes were treated with intrapleural instillations of UK. Six patients had previously undergone unsuccessful conventional tube drainage. Loculation was suggested by persistent fluid despite an adequate trial of simple drainage, radiographic demonstration of septation, or drainage of a volume of fluid far less than expected by a computed tomography scan. After instillation of a UK solution, the tubes were clamped for 30 to 180 min and then placed back to suction. Five pleural cavities with disease 6 to 18 days old showed complete resolution, and clinical improvement occurred. Three pleural processes showed improvement and one showed no improvement, with disease ranging from 23 days to 3 months. No complications were seen. These results suggest that UK instillations may enhance tube drainage of loculated pleural fluid in the early phase, before fibrosis has developed.