OBJECTIVES:To assess the efficacy of ramelteon in preventing delirium, an acute neuropsychiatric condition associated with increased morbidity and mortality, in the perioperative, ICU setting. DESIGN:Parallel-arm, randomized, double-blinded, placebo-controlled trial. SETTING:Academic medical center in La Jolla, California. PATIENTS:Patients greater than or equal to 18 years undergoing elective pulmonary thromboendarterectomy. INTERVENTIONS:Ramelteon 8 mg or matching placebo starting the night prior to surgery and for a maximum of six nights while in the ICU. MEASUREMENTS AND MAIN RESULTS:Incident delirium was measured twice daily using the Confusion Assessment Method-ICU. The safety outcome was coma-free days assessed by the Richmond Agitation-Sedation Scale. One-hundred twenty participants were enrolled and analysis completed in 117. Delirium occurred in 22 of 58 patients allocated to placebo versus 19 of 59 allocated to ramelteon (relative risk, 0.8; 95% CI, 0.5-1.4; p = 0.516). Delirium duration, as assessed by the number of delirium-free days was also similar in both groups (placebo median 2 d [interquartile range, 2-3 d] vs ramelteon 3 d [2-5 d]; p = 0.181). Coma-free days was also similar between groups (placebo median 2 d [interquartile range, 1-3 d] vs ramelteon 3 d [2-4 d]; p = 0.210). We found no difference in ICU length of stay (median 4 d [interquartile range, 3-5 d] vs 4 d [3-6 d]; p = 0.349), or in-hospital mortality (four vs three deaths; relative risk ratio, 0.7; 95% CI, 0.2-3.2; p = 0.717), all placebo versus ramelteon, respectively. CONCLUSIONS:Ramelteon 8 mg did not prevent postoperative delirium in patients admitted for elective cardiac surgery.