Background: Neurosurgical patients requiring short term postoperative mechanical ventilation frequently need sedatives and analgesics to facilitate their care. Aim: The present study compared the efficacy of dexmedetomidine and propofol for sedation in neurosurgical patients for postoperative mechanical ventilation. Design: Prospective randomised study. Materials and Methods: 60 patients of either sex, aged 18 to 60 years, ASA physical status I or II, preoperative GCS 15, undergoing neurosurgery and requiring short term postoperative ventilation were included. The patients were randomly divided into two groups of 30 each. Group I received dexmedetomidine 1 μgkg–1 over 10 minutes followed by maintenance infusion at a rate of 0.2–0.5 μgkg–1hr–1. Group II received propofol as a bolus of 1 mgkg–1 initially, followed by an infusion of 0.5–1 mgkg–1hr–1. Additional analgesia, if required, was provided by fentanyl infusion. Heart rate, mean arterial pressure, central venous pressure, oxygen saturation, sedation level , fentanyl requirement, ventilation and extubation time were recorded. Results: Adequate sedation level was achieved with both drugs. Ramsay sedation score was 3.88 ± 0.39 and 4.04 ± 0.47 for dexmedetomidine and propofol, respectively, (p=0.152). Total fentanyl dose in the dexmedetomidine group was 33.5 ± 7.51 μg compared to 72.2 ± 18.15 μg in the propofol group, (p<0.05). Patients who received dexmedetomidine infusion had significantly lower heart rates compared to patients who received propofol infusion, (p<0.05). No difference was found in mean arterial pressures of two groups. Extubation times were similar and rapid with the use of both sedative agents (27.4 ± 9.53 minutes for Group I and 30.36 ± 10.66 minutes for Group II, p>0.05). No adverse events related to sedative infusions occurred in either group. Conclusion: Dexmedetomidine is safe and equally effective agent compared to propofol for sedation of neurosurgical mechanically ventilated patients with good hemodynamic stability and extubation time as rapid as propofol.