Background: The co-administration of ketamine and propofol (CoKP) is thought to maximize the beneficial profile of each medication, while minimizing the respective adverse effects of each medication. Objective: Our objective was to compare adverse events between ketamine monotherapy (KM) and CoKP for procedural sedation and analgesia (PSA) in a pediatric emergency department (ED). Methods: This was a prospective, randomized, single-blinded, controlled trial of KM vs. CoKP in patients between 3 and 21 years of age. The attending physician administered either ketamine 1 mg/kg i.v. or ketamine 0.5 mg/kg and propofol 0.5 mg/kg i.v. The physician could administer up to three additional doses of ketamine (0.5 mg/kg/dose) or ketamine/propofol (0.25 mg/kg/dose of each). Adverse events (e.g., respiratory events, cardiovascular events, unpleasant emergence reactions) were recorded. Secondary outcomes included efficacy, recovery time, and satisfaction scores. Results: Thirty-two patients were randomized to KM and 29 patients were randomized to CoKP. There was no difference in adverse events or type of adverse event, except nausea was more common in the KM group. Efficacy of PSA was higher in the KM group (99%) compared to the CoKP group (90%). Median recovery time was the same. Conclusions: We found no significant differences in adverse events between the KM and CoKP groups. While CoKP is a reasonable choice for pediatric PSA, our study did not demonstrate an advantage of this combination over KM.