Rationale: Intrapleural tPA/DNase therapy for pleural infection given at the time of diagnosis has been shown to significantly improve radiological outcomes. Published cases are limited to a single randomized control trial and few case reports only. Objective: Multinational observation series to evaluate the pragmatic "real-life" application of tPA/DNase treatment for pleural infection in a large cohort of unselected patients. Methods: All patients from eight centers who received intrapleural tPA/DNase for pleural infection between January 2010 and September 2013 were included. Measured outcomes included treatment success at 30 days, volume of pleural fluid drained, improvement in radiographic pleural opacity and inflammatory markers, need for surgery and adverse events. Measurement and Main Results: Of 107 patients treated, the majority (92.3%) were successfully managed without necessitating surgical intervention. No patients died from pleural infection. Most (84%) patients received tPA/DNase more than 24 hours after failing to respond to initial conservative management with antibiotics and thoracostomy. tPA/DNase increased fluid drained from 250mL(median, IQR 100-654) in the preceding 24h to 2475mL(1800-3585) in the 72h following commencement of intrapleural therapy (p<0.05). A corresponding clearance of pleural opacity on chest radiographs from 35% (median, IQR 25-31) to 14% (7-28) of the hemithorax (p<0.001), and significant reduction in C-reactive protein (p<0.05) were observed. Pain necessitating escalation of analgesia occurred in 19.6% and non-fatal bleeding in 1.8% of patients. Conclusion: This largest series of intrapleural tPA/DNase therapy provides important evidence that the treatment is effective and safe especially as a 'rescue therapy' in patients who failed to initially respond to antibiotics and thoracostomy drainage.