Background Many patients admitted to medical intensive care units require mechanical ventilation to assist with respiratory management. Unplanned extubations of these patients are associated with poor outcomes for patients and organizations. No previous research has investigated the role of standardized protocols in unplanned extubations when examined in conjunction with traditional risk factors. Objective To identify risk factors associated with unplanned extubation among patients receiving mechanical ventilation and determine degree of compliance with pain, sedation, and weaning protocols. Methods A prospective cohort study design was used. Data on all patients admitted to the medical intensive care unit who required mechanical ventilation were gathered daily. Additional data were gathered on those patients who experienced unplanned extubation. Descriptive, correlational, and regression analyses were performed. Results Weaning protocols were a significant predictor of unplanned extubation: patients who had weaning protocols ordered and followed were least likely to experience unplanned extubation. Only 10% of the 190 patients in the study required reintubation, resulting in a significantly shorter ventilation time and unit length of stay among the unplanned extubation group. Conclusions Weaning protocols were associated with decreased incidence of unplanned extubation. Use of standardized protocols was feasible, as compliance among health care providers was high when protocols were medically prescribed. The reintubation rate in this study was low and associated with a significantly shorter ventilatory period and unit length of stay in the unplanned extubation group. (American Journal of Critical Care. 2011;20:304- Within our institution, an ongoing quality improvement project indicated that unplanned extubation continued to occur despite implementation of sedation, pain management, and weaning protocols that addressed factors reported in the literature to be associated with unplanned extubation. Additional investigation was needed to explore factors associated with unplanned extubation. Therefore, a research project was initiated with the following study aims: (1) to identify factors associated with unplanned extubation among patients admitted to the MICU who are receiving mechanical ventilation and (2) to determine the degree of compliance of physicians and nurses with sedation, pain, and weaning protocols.