INTRODUCTION Enteral clonidine represents a potentially less costly alternative to dexmedetomidine for sedation in intensive care unit (ICU) patients. This study describes our practice of transitioning selected adult ICU patients from dexmedetomidine to clonidine with a focus on efficacy, safety, and drug acquisition costs. METHODS We conducted a single-center prospective observational pilot study from January through March 2014. Consecutive patients 18 years and older treated with dexmedetomidine and transitioned to clonidine were followed. The transition was assessed in five phases: dexmedetomidine maintenance, transition, clonidine maintenance, clonidine taper, and post clonidine. Efficacy data included any occurrence of significant pain, excessive agitation or oversedation, delirium, and need for ancillary psychoactive medications. Safety data included any occurrence of bradycardia, hypotension, new second- or third-degree atrioventricular node blockade, and clonidine withdrawal syndrome. Drug acquisition cost avoidances were estimated using average wholesale price. RESULTS Twenty patients were evaluated. Fifteen (75%) were successfully transitioned from dexmedetomidine within 48 hours of starting clonidine. The initial and maintenance clonidine regimens were 0.3 mg every 6 hours. Clonidine was the sole α2A -receptor agonist administered for 45 hours while in the ICU and for 54 hours outside the ICU. Fentanyl requirements were lower when clonidine was administered as the sole α2A -receptor agonist as compared to dexmedetomidine alone (387 vs. 891 μg/day, p = 0.03). Otherwise, there were no statistically significant differences in efficacy data during the dexmedetomidine and clonidine maintenance phases. No statistically significant differences in safety data were observed. Clonidine withdrawal syndrome criteria were met in one patient. The potential drug acquisition cost avoidance was $819-$2338 per patient during the 3-month study. CONCLUSIONS Transitioning from dexmedetomidine to clonidine may be an efficacious, safe, and less costly method of maintaining α2A -receptor agonist therapy in critically ill adults; these results warrant confirmation in expanded studies.