Abstract Background: The prevalence of delirium reported in medical and surgical ICU has varied from 20% to 80%, depending upon severity of illness observed and diagnostic methods used. Aim of Study: To examine the efficacy and safety of Quetiapine in the prophylaxis against delirium in high risk critically ill patient and comparing its effect with haloperidol. Patients and Methods: This study was conducted on a total of 70 adult, conscious patients, who were admitted to Critical Care Medicine Department of El-Demerdash Hospital, Shebein Elkom Teaching Hospital. Patients were categorized into two groups using conventional method of randomization from the day of admission: Group I for high risk patient whom received 0.5-1.5mg/day haloperidol for prophylaxis of delirium till onset of delirium, acute attack resolved and ICU discharge. Group II for high risk patient whom received 25-75mg/day Quetiapine for prophylaxis of delirium till onset of delirium, acute attack resolved and ICU discharge. Results: Frequent assessment of both groups at 12 hrs interval for the onset of delirium by using CAM-ICU score revealed significantly lower incidence of delirium in group II (17.1%) than in group I (40%), p=0.034. Further, all survived patients in both groups showed negative CAM score at the time of discharge. Monitoring the occurrence of side effects in both groups showed significantly greater incidence of extrapyramidal effects, prolonged QT and hypotension in group I (2.9%, 8.6%, 14.3% respectively) compared to group II (0.0%, 0.0%, 2.9% respectively) (p=0.032). Conclusion: This study reflects the advantage of using Qutepiene as a newer antidelrium therapy over Halopredol as a prophylaxis against ICU delirium in high risk patients. Qutiepiene, compared to Haloperidol is less in developing serious side effect e.g. prolonged QT interval, extrapyramidal manifestations and hypotension.