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RATIONALE When drainage of complicated pleural space infections alone fails, there exists two strategies in surgery and dual agent-intrapleural fibrinolytic therapy; however, studies comparing these two management strategies are limited. OBJECTIVE To determine the outcomes of surgery versus fibrinolytic therapy as the primary management for complicated pleural space infections. METHODS A retrospective review of adults with a complicated pleural space infection managed with surgery or fibrinolytics between 1/2015-3/2018 within a multicenter, multistate hospital system was performed. Fibrinolytics was defined as any dose of dual-agent fibrinolytic therapy and standard fibrinolytics as 5-6 doses twice daily. Treatment failure was defined as persistent infection with a pleural collection requiring intervention. Crossover was defined by any fibrinolytics after surgery or surgery after fibrinolytics. Logistic regression with inverse probability of treatment weighting (IPTW) were employed to account for selection bias effect of management strategies in treatment failure and crossover. RESULTS We identified 566 patients. Surgery was the initial strategy in 55% (311/566). The surgery group had less additional treatments [surgery: 10% (32/311) versus fibrinolytics: 39% (100/255), p<0.001], treatment failures [surgery: 7% (22/311) versus fibrinolytics: 29% (74/255), p<0.001], and crossovers [surgery: 6% (20/311) versus fibrinolytics: 19% (49/255), p<0.001]. Logistic regression analysis with IPTW demonstrated a lower odds of treatment failure with surgery compared to any fibrinolytics [OR=0.20; 95% CI=0.10-0.30, p<0.001] and compared to standard fibrinolytics [OR=0.20; 95% CI=0.11-0.35, p<0.001]. CONCLUSION While there is a lack of consensus as to the optimal management strategy for patients with a CPSI, in surgical candidates operative management may offer more benefits and could be considered early in the management course. However, our study is retrospective and non-randomized; thus, prospective trials are needed to explore this further.