Dexmedetomidine, a selective α2 adrenergic receptor agonist, exhibits sedative, analgesic, anxiolytic, and sympatholytic effects, and may aid in controlling agitation in the intensive care unit (ICU). At our hospital (Barnes-Jewish Hospital, St. Louis, MO), dexmedetomidine is commonly used as a sedative in the medical ICU. Predictors of dexmedetomidine intolerance or failure have not yet been defined. Describe the rate of dexmedetomidine infusion intolerance/failure and identify patient predictors of intolerance/failure. This retrospective single-center cohort study evaluated 75 mechanically ventilated adults who received dexmedetomidine infusion. Patients were included in the study if they were aged ≥ 18 years; mechanically ventilated for > 24 hours; received dexmedetomidine infusion for ≥ 1 hour following > 24 hours of continuous infusions of midazolam, fentanyl, or propofol; and were admitted to our medical ICU between August 1, 2009 and August 1, 2010. Multivariate logistic regression analysis was performed to identify independent predictors of intolerance/failure. A total of 85 episodes of dexmedetomidine infusion were analyzed (75 total patients). Eighteen episodes (21%) met the criteria for intolerance/failure and 67 episodes (79%) met the criteria for tolerance/success. The median duration of mechanical ventilation, total dexmedetomidine infusion time, and ICU length of stay did not differ between groups. Nonblack race was the only variable independently associated with treatment failure or intolerance in the logistic regression analysis. Twenty-one percent of dexmedetomidine infusion episodes met the criteria for intolerance/failure. No predictors of intolerance/failure were found to be clinically significant.