The main target is evacuation; however, with evidence about the value of intrapleural instillation of different fibrinolytic agents still under evaluation, our aim was comparing the effectiveness and safety of intrapleural instillation of sodium bicarbonate (NaHCO 3 ) in comparison with urokinase in patients with infected pleural effusion. Methods: Our prospective cohort study included 40 patients with complicated empyema; the diagnosis was based on analysis of aspirated fluid in association with radiological and bacteriological culture. The patients were subjected to instillation of two different fibrinolytic agents; the first one was NaHCO 3 , the second was urokinase. Results:The commonest underlying chest infection that was visualized by CT was pneumonia 70%. Nearly half of cases had community-acquired infection (45%), and more than half of them (55%) had anaerobic infection, and only five cases had TB pleural effusion based on ADA-positive, tuberculin skin test in addition to Abram's needles closed biopsy. The rate of repeated therapeutic thoracentesis success in each group was 85%; 80% in NaHCO 3 group, and 90% in urokinase group, both of them was significantly equal, P=0.37. Moreover, the frequency of complications in all patients was less than 13%, hence hemothorax and iatrogenic pneumothorax was 12.5%, and only 10% of cases were admitted in ICU after the maneuver, with insignificant difference in between the groups. However, looking at the smaller rate of RTT failure of NaHCO 3 or urokinase, the logistic regression model showed that RTT-NaHCO 3 was insignificantly related to failure in both unadjusted and adjusted models, P=0.37 and 0.32, respectively, and only smoking habits increase the likelihood of failure 9-fold (OR=8.9, P=0.04) with respect to age, sex, and treatment methods. Conclusion:The efficacy of repeated therapeutic thoracentesis (RTT) with intrapleural instillation of NaHCO 3 was effective and safe, the same as urokinase, with consideration that NaHCO 3 was much more available and affordable than urokinase.