Study objective: This study was conducted to investigate the frequency and severity of adverse effects, specifically emergence phenomena, experienced by patients receiving intravenous ketamine with or without midazolam for sedation in a pediatric emergency department. Methods: Patients aged 4.5 months to 16 years receiving ketamine sedation were prospectively enrolled in a double-blind, randomized, controlled study at a university-affiliated children's hospital-pediatric ED. All patients received ketamine (1 mg/kg) and glycopyrrolate (5 μg/kg) intravenously. Patients were randomly assigned to receive midazolam (0.1 mg/kg) intravenously or no midazolam. Total time of sedation, sedation efficacy, and adverse effects were recorded. Adverse effects were compared between patients receiving ketamine versus those who received ketamine and midazolam. Additional comparisons were made based on age and number of ketamine doses administered. Results: Two hundred sixty-six patients were studied; 129 received ketamine and 137 patients received ketamine and midazolam. Time of sedation and efficacy of sedation were equivalent between groups. Overall, adverse effects with ketamine sedation included respiratory events (12 [4.5%]), vomiting (50 [18.7%]), emergence phenomena in the pediatric ED (71 [26.7%]), and emergence phenomena at home (60 [22.4%]). Significant emergence phenomena in the pediatric ED (ie, nightmares, hallucinations, and severe agitation) occurred in 7.1% of the ketamine group and in 6.2% of the ketamine-midazolam group, a rate difference of 0.8 (95% confidence interval [Cl] -5.3 to 7.0). The addition of midazolam led to an increased incidence of oxygen desaturation events (ketamine 1.6% versus ketamine-midazolam 7.3%; rate difference-5.7, 95% Cl-10.6 to -0.9) but a decreased incidence of vomiting (ketamine 19.4%, ketaminemidazolam 9.6%, rate difference 9.8, 95% Cl 1.4 to 18.2). The incidence of emergence phenomena and significant emergence phenomena was not affected by the addition of midazolam. However, the addition of midazolam was associated with more agitation in the pediatric ED in children 10 years or older (ketamine 5.7% versus ketamine-midazolam 35.7%; rate difference -30.0, 95% Cl-10.7 to -49.3). Age breakdown further showed 6.3% (95% Cl 0.9 to 11.6) more episodes of oxygen desaturation in the ketamine-midazolam group in children younger than 10 years, and 12.1% (95% Cl 1.5 to 22.6) more vomiting episodes in the ketamine group in children younger than 10 years. Conclusion: Ketamine and combined ketamine and midazolam provided equally effective sedation. The addition of midazolam did not alter the incidence of emergence phenomena. Vomiting occurred more frequently in the ketamine only group, whereas oxygen desaturation occurred more frequently in the ketaminemidazolam group. These findings were more pronounced in patients younger than 10 years. Parental and physician satisfaction remained high for all patients receiving intravenous ketamine sedation.