Purpose: To examine the influence of substituting intranasal (IN) midazolam (MID) for oral ( PO) MID, within the three-drug combination of meperidine ( MEP), hydroxyzine (H) and MID, on sedation treatment outcomes. Methods: A retrospective, cross-sectional analysis examined patient variables and sedation outcomes in 508 pediatric dental patients sedated by single- and multi-drug seda-tion regimens (MEP-H; MEP-H-(PO)-MID; MEP-H-(IN)-MID; single-agent MID). The outcome assessment examined sedation visit effectiveness, sedation treatment completion, treatment time and medication administration to discharge time. Multi-variable logistic regression analyses assessed predictive variables associated with sedation visit effectiveness. Results: Both three-drug combinations (MEP-H-(PO)-MID; MEP-H-(IN)-MID) were used for behavior guidance in children of a similar age (median age=7.1 and 6.5 years, respectively, for the two drug combinations) and weight (median weight = 23.7 and 23.5 kg, respectively, for the two drug combinations). These three-drug com-binations had a higher likelihood of sedation effectiveness over the reference sedation regimen of single-agent midazolam ( MEP-H-(PO)-MID adjusted odds ratio [OR] = 2.65; 95 percent confidence interval [95% CI]=1.09 to 6.45; P=0.032; and MEP-H(IN)- MID OR=2.08; 95% CI=1.03 to 4.18; P=0.039). MEP-H-(IN)MID was asso-ciated with a shorter medication administration to discharge time for patients by 23 minutes (interquartile range [IQR]=9.5 to 34 minutes) compared to MEP- H-(PO) MID (P<0.05) while providing a comparable number of teeth treated (median=five). All sedation drug regimens, including MEP-H-(IN)MID, had high levels of oxygen saturation during all sedation appointments. Conclusion: Substituting IN for PO MID in MEP- H-MID was associated with a shorter total time to discharge while demonstrating comparable efficacy during sedation. ( J Dent Child 2023;90(3):139-46)