Background. Persistent air leak (PAL; defined as air leak > 5 days) after major pulmonary resection is prevalent and associated with significant morbidity. This study examines an incompletely characterized treatment for the management of PAL, chemical pleurodesis. Methods. A retrospective case-control study examining all isolated lobectomies and bilobectomies by thoracotomy was performed. The PALs (1997 to 2006) and controls (2002 to 2006) were identified from a prospective database. Incidence, risk factors, management, and outcome were defined. Results. Over 9 years, 78 PALs were identified in 1,393 patients (5.6%). Controls consisted of 700 consecutive patients. Propensity score analysis matching case and controls showed no predictive risk factors for air leak using a logistic regression model. Univariate analysis demonstrated that female gender, smoking history, and forced vital capacity were predictive risk factors. Treatment of PAL consisted of observation (n = 33, 42.3%), pleurodesis (n = 41, 52.6%), Heimlich valve (n = 3, 3.8%), and reoperation (n = 1, 1.3%). Seventy-three patients (93.6%) required no further intervention. One patient required a muscle flap, one readmission for pneumothorax, and one empyema resulting in death. Sclerosis was successful in 40 of 41 patients (97.6%). Mean time to treatment was 8.4 +/- 3.6 days, mean duration of air leak was 10.7 +/- 4.5, and mean duration of air leak postsclerotherapy was 2.8 +/- 2.2 days. Postoperative pneumonia occurred with increased frequency in PAL patients (6 of 45 [13.3%] vs 34 of 700 [4.9%], p = 0.014). PAL was associated with increased length of stay (14.2 vs 7.1 days, p < 0.001) and time with chest tube (11.5 vs 3.4 days, p < 0.001). Conclusions. Air leaks remain an important cause of morbidity. Pleurodesis is an effective option in management of PAL after major pulmonary resection. (Ann Thorac Surg 2010;89:891-8) (C) 2010 by The Society of Thoracic Surgeons