Alteplase and pulmozyme (DNase) administered intrapleurally have revolutionised the management of pleural infection in the last decade. However, the use of intrapleural fibrinolytic has not been well established in high risks patients. Here, we describe 2 patients with high risk of bleeding due to recent surgery who developed empyema; successfully treated with these medications. The first patient was a 36-year-old female post oesophagectomy for oesophageal carcinoma, complicated with anastomotic leak and empyema; and the second patient was a 56-year-old female post percutaneous nephrolithotomy for right obstructive uropathy who developed right-sided empyema. Both patients were treated successfully with 3 doses of intrapleural alteplase 2.5 mg and DNase 5 mg without any major adverse effects. This case report adds to the current literature on the safety of intrapleural fibrinolytics and highlights that lower doses of alteplase in combination with pulmozyme is efficacious and may be considered in high-risk patients.