Objective: To assess the feasibility and safety of delivering early goal-directed sedation compared with standard sedation. Design: Pilot prospective, multicenter, randomized, controlled trial. Setting: Six ICUs. Patients: Critically ill adults mechanically ventilated for greater than 24 hours. Interventions: Patients randomized to early goal-directed sedation received a dexmedetomidine-based algorithm targeted to light sedation (Richmond Agitation Sedation Score of -2 to 1). Patients randomized to standard sedation received propofol and/or midazolam-based sedation as clinically appropriate. Measurements and Main Results: The main feasibility outcomes were time to randomization and proportion of Richmond Agitation Sedation Score assessments in the first 48 hours in the light and deep sedation range. Safety outcomes were delirium-free days, vasopressor and physical restraints use, and device removal. Randomization occurred within a median (interquartile range) of 1.1 hours (0.46-1.9) after intubation or ICU admission for out of ICU intubation. Patients in the early goal-directed sedation (n = 21) mean (SD) Acute Physiology and Chronic Health Evaluation II score was 20.2 (6.2) versus 18.6 (8.8; p = 0.53) in the standard sedation (n = 16). A significantly higher proportion of patients was lightly sedated on days 1, 2, and 3 (12/19 [63.2%], 19/21 [90.5%], and 18/20 [90%] vs 2/14 [14.3%], 8/15 [53.3%], and 9/15 [60%]; p = 0.005, 0.011, 0.036) and more Richmond Agitation Sedation Scale assessments between (-2 and 1), in the first 48 hours (203/307 [66%] versus (74/197 [38%]; p = 0.01) in the early goal-directed sedation versus standard sedation, respectively. Early goal-directed sedation patients received midazolam on 6 of 173 (3.5%) versus 4 of 114 (3.5%) standard sedation patient-days when dexmedetomidine was given. Propofol was given to 16 of 21 (76%) of early goal-directed sedation versus 16 of 16 (100%) of standard sedation patients (p = 0.04). Early goal-directed sedation patients had 101 of 175 (58%) versus 54 of 114 (47%; p = 0.27) delirium-free days and required significantly less physical restraints 1 (5%) versus 5 (31%; p = 0.03) than standard sedation patients. There were no differences in vasopressor use and self-extubation. Conclusions: Delivery of early goal-directed sedation was feasible, appeared safe, achieved early light sedation, minimized benzodiazepines and propofol, and decreased the need for physical restraints. The findings of this pilot study justify further investigation of early goal-directed sedation.