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STUDY OBJECTIVE Dexmedetomidine, which is commonly used for procedural sedation and as adjunct to general anesthesia for ambulatory procedures, may affect patient discharge from the post-anesthesia care unit (PACU). We hypothesized that intraoperative dexmedetomidine use in ambulatory surgery is associated with delayed discharge from the PACU and that this is modified by surgical duration and anesthesia type. DESIGN Retrospective cohort study. SETTING Academic medical center. PATIENTS 130,854 adult patients undergoing ambulatory surgery between 2008 and 2018. INTERVENTIONS Intraoperative administration of dexmedetomidine. MEASUREMENTS The primary outcome was PACU length of stay. In secondary and exploratory analyses, we examined dose-dependency, effect modification by duration of surgery and anesthesia type, effects of timing of dexmedetomidine administration, and PACU discharge delays. MAIN RESULTS Dexmedetomidine was associated with a prolonged PACU length of stay (adjusted absolute difference [ADadj] 15.0 min; 95%CI 12.7-17.3; p < 0.001). This effect was dose-dependent (p-for-trend < 0.001), magnified in surgeries of less than one hour (ADadj 20.7 min; 95%CI 16.7-24.7; p < 0.001) and in patients undergoing monitored anesthesia care compared to general anesthesia (ADadj 16.8 min; 95%CI 14.1-19.6; p < 0.001). The effect was more pronounced if dexmedetomidine was administered within the last 60 min of surgery (ADadj 18.7 min; 95%CI 15.7-21.7; p < 0.001). Dexmedetomidine was associated with discharge delays due to cardiovascular complications (ORadj 2.27; 95%CI 1.59-3.24; p < 0.001) and over-sedation (ORadj 1.28; 95%CI 1.11-1.48; p < 0.001). In patients who received dexmedetomidine (n = 2901), the use of bolus doses only versus the combination of bolus and infusions, magnified the effects on PACU length of stay (ADadj 29.5 min per μg/kg; 95%CI 17.3-41.8 versus 18.1 min per μg/kg; 95%CI 11.4-24.8; p < 0.001). CONCLUSIONS The intraoperative administration of dexmedetomidine was dose-dependently associated with a prolonged PACU length of stay. Clinicians should judiciously titrate dexmedetomidine, especially when using this long-acting drug for monitored anesthesia care for shorter procedures.