Study objective: To compare the efficacy and complication profile of oral midazolam therapy and continuous-flow 50% nitrous oxide in alleviating anxiety during laceration repair in children 2 to 6 years old. Methods: We conducted a prospective, randomized clinical trial using 4 study groups who required laceration repair: (1) children who received standard care alone, which included comforting and topical anesthesia augmented with injected lidocaine if needed; (2) children who received standard care and oral midazolam; (3) children who received standard care and nitrous oxide; and (4) children who received standard care, oral midazolam, and nitrous oxide. Videotapes were blindly scored using the Observational Scale of Behavioral Distress-Revised (OSBD-R) to assess distress during baseline, wound cleaning, lidocaine injecting, suturing, and recovery. Adverse effects were noted during suturing and by parent questionnaires completed 24 hours after suturing and at suture removal. OSBD-R data were analyzed using repeated-measures analysis of variance. Adverse effect data were analyzed using categorical models. Results: Two hundred four subjects were enrolled (midazolam plus nitrous oxide 52, midazolam 51, nitrous oxide 51, standard care 50; mean patient age was 4.1 years; 66% were boys). Mean OSBD-R scores were lower for groups that received nitrous oxide during wound cleaning by 2.2 points (95% confidence interval [Cl] 1.1 to 3.2), lidocaine injecting by 2.5 points (95% Cl 1.4 to 3.5), and suturing by 2.9 (95% Cl 1.8 to 3.9). Adverse effects occurred more frequently, and recovery times were longer for groups that received midazolam. Conclusion: For facial suturing in 2- to 6-year-old children, regimens including continuous-flow nitrous oxide were more effective in reducing distress, and had fewer adverse effects and shorter recovery times than midazolam.