Purpose Infected pleural effusions are often inadequately treated with antibiotics alone. Thoracostomy tube drainage has become the standard of care. Increased viscosity and loculations however, often hinder complete drainage. An array of pleural fibrinolytics have been extensively studied in retrospective cohort studies and prospective trials with mixed results. A recent randomized control trial demonstrated success with a tissue plasminogen activator (tPA) and deoxyribonuclease (DNase) combined treatment, however the protocol required four separate medication administrations for three days, which may not be compatible with every clinical setting . The aim of this study is to compare the efficacy of a more easily administered protocol: combined tPA and DNase administration once per day for three days, to tPA monotherapy at a single institution. Materials and Methods A retrospective review of 25 patients with infected pleural effusions who received tPA and DNase were compared with historical controls that received tPA alone. Percent reduction of pleural effusion on chest radiographs between day 1 and day 7, change in white blood cell count (WBC) over time, need for additional tube placement, and length of hospital stay were recorded. Results Patients who received tPA and DNase once per day for three days demonstrated an average percent reduction of area of pleural effusion of 47% compared to 3% for those who received tPA alone (P= .042). The WBC count in the tPA and DNase group decreased by an average of 6132 cells/mcl over 7 days compared to 1078 cells/mcl in the tPa group (P< .01). There was no difference in the number of additional tubes or length of hospital stay. 5 patients in the tPA/DNase group reported severe pleuritic pain and respiratory distress requiring higher level monitoring, which was not observed in the literature supporting this study . Conclusion These results suggest that tPA and DNase once per day dosing is a sufficient alternative to the more intensive four times per day regiment that has been previously reported.