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This study was designed to evaluate and compare the efficacy and safety of nebulized dexmedetomidine, nebulized ketamine, and the combination of these drugs for premedication in pediatric outpatient dental surgeries.A prospective, randomized, double-blinded study was conducted in the Alexandria Main University Hospital after approval of the Medical Ethics Committee. Informed written consent was obtained from the patient’s parents. Sixty children classified as ASA physical status I and II and aged 3 to 6 years were enrolled in the study. Patients were randomly categorized into 3 equal groups. Group K was premedicated with nebulized ketamine (2 mg/kg), group D was premedicated with nebulized dexmedetomidine (2 μg/kg), and group DK was premedicated with combined nebulized dexmedetomidine and ketamine (1 μg/kg + 1 mg/kg). The primary end point was the level of sedation when the child was first seen in the operating room 30 minutes after sedation. The secondary end points were tolerance of mask induction, hemodynamic changes, analgesia, sedation at emergence, and wake-up behavior.Studied groups were comparable as regards demographic data (age, weight, sex, and ASA physical status, all P > 0.226) and patients’ acceptance of drugs (P = 0.968). Level of sedation at 30 minutes was significantly greater in group DK than in either group K (P = 0.003) or group D (P = 0.009). Group DK had the briefest recovery times, followed in order by group K and group D with progressively longer recovery times. Recovery times were significantly briefer in group DK than in either group K (P = 0.039) or group D (P < 0.001). Group DK had significantly briefer discharge times than group D (P < 0.001). Postoperative analgesia was significantly better in group DK compared with group K (P = 0.008).A nebulized combination of low-dose ketamine and dexmedetomidine produced more satisfactory sedation and provided a smoother induction of general anesthesia than nebulized ketamine or dexmedetomidine alone, with more rapid recovery and no significant side effects.