Background: The purpose of the study was to analyze the risk factors for failed extubation in subjects submitted to infratentorial craniotomy. Material/Methods: Patients aged over 18 years who received infratentorial craniotomy for brain tumor resection were consecutively included in this study. Perioperative variables were collected and analyzed. Univariate analyses and multiple logistic regression were used to derive factors related to failed extubation. Patients had follow-up care until either out of hospital or death. Results: Throughout the course of the study, 2118 patients were eligible and 94 (4.4%) suffered from extubation failure at some point during their hospital stay. Five factors were recognized as independent risk factors for postoperative failed extubation: craniotomy history, preoperative lower cranial nerve dysfunction, tumor size, tumor position, and maximum change in blood pressure (BP) during the operation. Failed extubation was related to a higher incidence rate of pneumonia, mortality, unfavorable Glasgow Outcome Scale score, longer stay in the neuro-intensive care unit (ICU) and hospitalization, and higher hospitalization costs compared with successful extubation. Conclusions: History of craniotomy, preoperative lower cranial nerve dysfunction, tumor size, tumor position, and maximum change in BP during the operation were independent risk factors related to postoperative failed extubation in patients submitted to infratentorial craniotomy. Extubation failure raises the incidences of postoperative pneumonia, mortality, and higher hospitalization costs, and prolongs neuro-ICU and postoperative length of stay.