Purpose: To compare the effectiveness and report on oral sedation-related events using three different multiagent regimens in pediatric patients up to 24 hours post-discharge. Methods: Sixty healthy 3- to 7-year-old patients were randomly allocated to 1 of 3 groups. Group 1 received midazolam, meperidine, and hydroxyzine (MZ/M/H; n equals 20). Group 2 received meperidine and hydroxyzine (M/H; n equals 20). Group 3 received midazolam and hydroxyzine (MZ/H; n equals 20). Nitrous oxide inhalation was concurrently used in all groups. After completion of sedation, the treating dentist answered survey 1 regarding the preoperative period until discharge. Parents completed 2 phone interviews at 8 and 24 hours post-discharge (surveys 2 and 3). Data analysis included chi-square, 1-way analysis of variance, and post-hoc tests (P<0.05). Results: Over-all, the 3 regimes were effective (90%). Group 1 showed a significant increase in slurring/difficulty speaking post-operatively and up to discharge (P=0.04). Groups 1 and 3 exhibited significantly greater difficulty walking on their own at discharge (P=0.02). Groups 1 and 2 experienced significantly increased lethargy (P=0.02) within 8 hours post-discharge. Overall musculoskeletal effects were significantly less prior to discharge in Group 2 (P=0.02), while gastrointestinal upset was significantly more in Group 1 at 24 hours post-discharge (P=0.01). Conclusions: This randomized clinical trial demonstrated that oral sedation regimens containing different combinations of midazolam, meperidine, and hydroxyzine are effective and relatively safe. Postoperative monitoring remains essential up to 24 hours. Longer postoperative monitoring may be required when a 3-medication regimen is used.