Background: Intrapleural fibrinolytics installation is considered an alternative method to aggressive operative intervention. This conservative medical management may decrease morbidity and mortality that were recorded with surgery. Our study investigates the outcome of tissue plasminogen activator (TPA), alteplase, and streptokinase (SK) as a treatment for stage II of empyema. Methods: This study prospectively evaluated 38 patients that had stage II of empyema. The patients were divided into two groups with installing one fibrinolytic protocol into a chest tube for each group: group A, (TPA) and group B, (SK). The evaluation was based upon clinical examination and radiological findings for the efficacy of each protocol. Results: There were no differences in baseline characteristics between both groups. There was a significant improvement after 1st, where 11 patients (52.4%) improved in the TPA group with only 3 patients (17.6%) in the SK group. TPA group showed 100% success, on the other hand, SK Group had 2 patients’ failure (11.8%) and surgical intervention was necessary for them. Hemorrhagic complications were 9.5% and 17.6% for TPA and SK respectively. Finally, there was a significantly prolonged duration of mean hospital stay with SK therapy (5.48 vs 8.59 days). Conclusions: Both fibrinolytic protocols were effective and safe for empyema management, but Alteplase had a better outcome.