Background and Objectives: Post-operative mechanically ventilated patient in the intensive care unit (ICU) frequently need sedation and analgesia to facilitate care. Inadequate Sedation in patients admitted to the ICU after surgery leads to patient discomfort, ventilator asynchrony, accidental device removal, and increase metabolic demands during respiration. Careful drug selection for sedation by the ICU team is essential so that patients can be easily weaned from mechanical ventilation after stopping sedation to achieve lesser duration of mechanical ventilation and to decrease ICU stay. Dexmedetomidine, a short-acting alpha-2-agonist, has anxiolytic, anesthetic, hypnotic, and analgesic properties.Propofol is recommended for the short-term (<24 h) treatment of anxiety in post-operative mechanically ventilated patients. The objective of this study was to compare the efficacy and safety of dexmedetomidine versus propofol for post-operative mechanically ventilated patients in ICU before weaning from mechanical ventilation. Methodology: Thirty patients aged above 20 years after major abdominal or pelvic surgeries requiring at least 6 hrs artificial ventilation admitted to ICU were included as subjects and they were randomly divided into two groups of fifteen each. Group D received Dexmedetomidine, a loading dose of 2.5 μg/kg and a maintenance dose of 0.5 μg/kg/hr and Group P received Propofol, a loading dose of 1 mg/kg and a maintenance dose of 0.5 mg/kg/hr. Both the groups were compared for level of sedation using Ramsay sedation score, hemodynamic variables, safety profile and fentanyl requirement to achieve adequate analgesia. Results: Ramsay sedation score was within the desired level (2-4) in both Dexmedetomidine and Propofol groups (p>0.05). Patients who received Dexmedetomidine infusion had significantly decreased heart rates when compared to patients who received Propofol infusion (p<0.00). Total Fentanyl dose requirement was significant in Propofol group (66.3 ± 10.1 μg) when compared to Dexmedetomidine group. (31.0 ± 9.5 μg; p=0.001). Conclusion: Dexmedetomidine and Propofol are safe sedative drugs for post-operative mechanically ventilated patients.To compare with Propofol, Dexmetomidine induces less sedation level with the same duration of mechanical ventilation and has its own analgesic effect and shortens the length of patient's stay in ICU. Bradycardia was noted more frequently in Dexmedetomidine while arterial hypotension, general malaise and delirium in Propofol group.Fentanyl requirement was more with Propofol group.