Introduction: Management of complicated parapneumonic effusions (CPEs) and empyema is difficult, as no clear guidelines exist. The use of intrapleural fi brinolytics has shown promising results in several studies. Objective: The objective was to study the safety and efficacy of streptokinase (STK) in multiloculated empyema in children. Patients and Methods: This is a comparative descriptive study which included initial 50 patients in the STK group and subsequent 50 patients in the placebo group. Intrapleural STK was given twice daily at a dose of 5000 IU/kg for 7 days. In the placebo group, 50-ml normal saline was instilled intrapleurally through the chest tube. The patients were assessed for safety and efficacy of STK. The efficacy of STK was assessed by expansion of lung on chest-X-ray and breakage of loculi on thoracic ultrasound. Success of STK therapy was assessed by decrease in number of surgical referrals for decortication. Results: The amount of intercostal tube drainage output as well as mean duration of its insertion was statistically significant in the STK group. The percentage of overall success was 84% of patients in the STK group versus 52% in the placebo group, and the difference was statistically significant. Decortication was required in 24% of patients in the STK group and 60% of patients in the placebo group, which was again statistically significant. Conclusion: Instillation of STK in multiloculated empyema is safe and effective and decreases referrals for surgery. Awareness needs to be created among health-care workers for prompt diagnosis and treatment of patients of CPE and empyema with intrapleural fibrinolytics before surgical referral.