Objectives: To evaluate the impact of a nurse-driven sedation protocol on the length of mechanical ventilation, total daily doses of sedatives, and complications of sedation. Design: A single-center prospective before and after study was conducted from October 2010 to December 2013. Setting: Twelve-bed surgical and medical PICU of the university-affiliated hospital in Nantes, France. Patients: A total of 235 patients, between 28 days and 18 years old, requiring mechanical ventilation for at least 24 hours were included in the study; data from 194 patients were analyzed. Interventions: During the first study phase, no protocol was used. During the second phase, patients were sedated according to a nurse-driven protocol. Measurements and Main Results: In the whole population, the length of mechanical ventilation did not differ between protocol and control groups (protocol, 4 [3-8] vs control, 5 [3-7.5]; p = 0.44). Analyzing age subgroups, the length of mechanical ventilation was significantly shorter in the protocol group than in the control group in children older than 12 months (4 [3-8] vs 5 [2.75-11.25] d; p = 0.04). Daily dose of midazolam decreased during the protocol phase compared with the control phase (1 [0.56-1.8] and 1.2 [0.85-2.4] mg/kg/d, respectively; p = 0.02). No differences were shown regarding other daily dose of drugs. In the control group, 68% of children had more than 20% of COMFORT-behavior scale assessment under the target (oversedation) versus 59% in the protocol group (p = 0.139). Conclusions: Implementation of a nurse-driven sedation protocol in a PICU is feasible and safe, allowed a decrease in daily dose of benzodiazepines, and decreased the duration of mechanical ventilation in older patients.