A 22-year-old Asian male presented with fever, non-productive cough, right-sided pleuritic chest pain and was found to have a large right hydropneumothorax. A chest tube was placed. Pleural fluid analysis revealed a lymphocytic predominant exudate and he was subsequently started on four-drug daily anti-tuberculosis therapy (isoniazid, ethambutol, rifampin, pyrazinamide). Pleural biopsy revealed acid-fast bacilli. Given his persistent pleural effusion, he was given four doses of intrapleural tissue plasminogen activator (tPA) and dornase alpha (DNase) via his chest tube over a period of 6 days resulting in clinical and radiologic improvement. Pleural biopsy and pleural fluid culture specimens later revealed Mycobacterium tuberculosis. Intrapleural tPA-DNase therapy has demonstrated improved resolution of infections and shortened hospitalizations for parapneumonic infectious effusions. However, there is little literature on the use of intrapleural fibrinolytics specifically for pleural tuberculosis associated effusions. Furthermore, the American Thoracic Society does not comment on therapeutic thoracentesis or intrapleural fibrinolytic therapy in their recommendations for treatment of pleural tuberculosis. In our case of pleural TB-associated hydropneumothorax, the use of intrapleural tPA-DNase therapy facilitated pleural fluid drainage and resulted in near-complete resolution of the effusion.