Background. Post-extubation negative-pressure pulmonary edema (NPPE) is a true anesthesia-related emergency presenting with acute respiratory distress and hypoxemia after removal of airway devices. This study investigated the incidence and associated risk factors for post-extubation NPPE during emergence. Methods and Results. This retrospective, matched case-control study was conducted by reviewing the post-anesthesia records in Tzu-Chi General Hospital, Taiwan. Patients reported of having acute hypoxemia (SpO2< 92%) shortly after removal of the endotracheal tube or supraglottic airway, associating with radiographic evidence of pulmonary edema and/or pink frothy sputum were identified as definite NPPE cases. The potential risk factors were compared with the matched controls, who were randomly selected from the same database. A total of 85561 patients received general anesthesia with airway instrumentation during the 8.5-year study period. A total of 16 patients were identified as definite cases of NPPE. Compared with the matched controls (n=131), males, active smokers, emergency operation, endotracheal intubation, use of desflurane and prolonged operation time carried significantly higher risks of developing NPPE (P< 0.05). Multivariate logistic regression analysis illustrated that active smoking (AOR 7.66, 95% CI 1.67-35.3; P=0.009) and endotracheal intubation (AOR 10.87, 95% CI 1.23-100; P=0.03) were the two most significant independent variables of post-extubation NPPE. Conclusion. We present the first clinical comparative study demonstrated that the overall incidence of NPPE immediately after extubation in the operating room is 0.019%. Our results highlight that active smokers and patients receiving endotracheal intubation general anesthesia are associated with significantly higher risks of developing NPPE following extubation in the operating room.