Objectives: Adjunctive anticholinergics are commonly administered during emergency department (ED) ketamine sedation in children under the presumption that drying oral secretions should decrease the likelihood of airway and respiratory adverse events. Pharmacologic considerations suggest that glycopyrrolate might exhibit a superior adverse effect profile to atropine. The authors contrasted the adverse events noted with use of each of these anticholinergics in a large multicenter observational database of ketamine sedations. Methods: This was a secondary analysis of an observational database of 8,282 ED ketamine sedations assembled from 32 prior series. The authors compared the relative incidence of six adverse events (airway and respiratory adverse events, laryngospasm, apnea, emesis, recovery agitation, and clinically important recovery agitation) between children who received coadministered atropine, glycopyrrolate, or no anticholinergic. Multivariable analysis using the specific anticholinergic as a covariate was performed, while controlling for other known predictors. Results: Atropine was associated with less vomiting (5.3%) than either glycopyrrolate (10.7%) or no anticholinergic (11.4%) in both unadjusted and multivariable analyses. Glycopyrrolate was associated with significantly more airway and respiratory adverse events (6.4%) than either atropine (3.3%) or no anticholinergic (3.0%) and similarly more clinically important recovery agitation (2.1% vs. 1.2 and 1.3%). There were, however, no differences noted in odds of laryngospasm and apnea. Conclusions: This secondary analysis unexpectedly found that the coadministered anticholinergic atropine exhibited a superior adverse event profile to glycopyrrolate during ketamine sedation. Any such advantage requires confirmation in a separate trial; however, our data cast doubt on the traditional premise that glycopyrrolate might be superior. Further, neither anticholinergic showed efficacy in decreasing airway and respiratory adverse events.