Intrapleural urokinase has not been evaluated systemically in terms of efficacy, safety, and cost of treatment in a large series of patients with complicated (parapneumonic) pleural effusions (CPE) and pleural empyemas (PE). Furthermore, the optimal dose and duration of treatment is not known. Twenty consecutive patients with multiloculated parapneumonic effusions (13 with CPE and 7 with PE), in whom a single chest tube failed to drain the fluid, were studied prospectively. The age of the patients ranged 15-92 yrs (median 51 yrs). Urokinase was administered intrapleurally, in a low single daily dose of 50,000 U in 100 mL normal saline via the chest tube. Previous intrapleural instillation of 100 mL normal saline failed to promote drainage in all patients. Urokinase enhanced drainage in all patients. Clinical and radiological improvement was noted in all but one patient. The mean (SD) volume of fluid significantly increased in the first 24 h post-urokinase (p<0.001). The number of urokinase instillations ranged 3-7 (median 5). Radiological evaluation showed excellent improvement in 13 of the 20 (65%) patients. Urokinase was well-tolerated in all patients. The clinical course of patients was uneventful at a mean follow-up of 15 months (range 6-30 months) later. Mean total cost of treatment was $530 +/- 34.6. Our results show that intrapleural instillation of small doses of urokinase is a cost-effective and safe mode of treatment of complicated pleural effusions and pleural empyema and could be the fibrinolytic of choice.