Objectives: The study aims to describe and compare the use of fibrinolytics in the diagnosis of pleural empyema (PE), the outcomes obtained, and the complications observed. Materials and Methods: A retrospective cohort study was conducted at the San Juan de Dios Hospital (Santiago, Chile) between January 2018 and June 2024. Characteristics of patients treated with intrapleural fibrinolysis were analyzed, including the etiology of pleural effusion, pleural fluid analysis, and microbiological results. Complications, the need for post-fibrinolysis surgery, and mortality were also evaluated. Results: A total of 67 cases were reviewed, of which 26.9% were women and 73.1% men, with a median age of 62 years. The main indication for the procedure was PE of pneumonic origin in 77.6% of the patients. The response rate to alteplase was 80%, compared to 58.8% in the group treated with streptokinase. The length of hospitalization was 27 and 20 days, respectively. Complications occurred in 14% of patients treated with alteplase and 5.9% with streptokinase. The overall mortality rate was 4.4%. Discussion: Pleural empyema has a mortality rate of up to 15% at 30 days. For patients who do not respond to antibiotics and pleural drainage, intrapleural fibrinolysis is a recommended option, although the rTPA + DNase regimen is not widely available in the public health system. Conclusion: The study presents national data on intrapleural fibrinolysis from a single-center cohort, highlighting the need to expand the technique.