Introduction: Randomized controlled trials suggest clinical outcomes may be improved with dexmedetomidine as compared with benzodiazepines; however, further study and validation are needed. The objective of this study was to determine the clinical effectiveness of a sedation protocol minimizing benzodiazepine use in favor of early dexmedetomidine. Methods: We conducted a before-after study including adult surgical and medical intensive care unit (ICU) patients requiring mechanical ventilation and continuous sedation for at least 24 hours. The before phase included consecutive patients admitted between 1 April 2011 and 31 August 31 2011. Subsequently, the protocol was modified to minimize use of benzodiazepines in favor of early dexmedetomidine through a multidisciplinary approach, and staff education was provided. The after phase included consecutive eligible patients between 1 May 2012 and 31 October 2012. Results: A total of 199 patients were included, with 97 patients in the before phase and 102 in the after phase. Baseline characteristics were well balanced between groups. Use of midazolam as initial sedation (58% versus 27%, P <0.0001) or at any point during the ICU stay (76% versus 48%, P <0.0001) was significantly reduced in the after phase. Dexmedetomidine use as initial sedation (2% versus 39%, P <0.0001) or at any point during the ICU stay (39% versus 82%, P <0.0001) significantly increased. Both the prevalence (81% versus 93%, P =0.013) and median percentage of days with delirium (55% (interquartile range (IQR), 18 to 83) versus 71% (IQR, 45 to 100), P =0.001) were increased in the after phase. The median duration of mechanical ventilation was significantly reduced in the after phase (110 (IQR, 59 to 192) hours versus 74.5 (IQR, 42 to 148) hours, P =0.029), and significantly fewer patients required tracheostomy (20% versus 9%, P =0.040). The median ICU length of stay was 8 (IQR, 4 to 12) days in the before phase and 6 (IQR, 3 to 11) days in the after phase (P =0.252). Conclusions: Implementing a sedation protocol that targeted light sedation and reduced benzodiazepine use led to significant improvements in the duration of mechanical ventilation and the requirement for tracheostomy, despite increases in the prevalence and duration of ICU delirium.