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Background: Mechanical ventilation and sedation are inextricably linked components of critical care that represent, what we do for the patients during their vulnerable course in Intensive Care Unit (ICU). Aims: The aim of this study is to compare the efficacy and safety of midazolam and dexmedetomidine in patients on mechanical ventilator with the help of Bispectral Index (BIS) monitoring and correlation of BIS with Sedation-Agitation Scale (SAS). Settings and Design: Prospective, observational, and comparative study. Materials and Methods: In this study, recruited patients were allocated into two groups of 14 patients each. Group A and Group B patients received injection dexmedetomidine and injection Midazolam, respectively. Hemodynamic parameters, time of extubation, duration of mechanical ventilation, and mortality were compared between two groups. Statistical Analysis: Mean and the standard deviation were calculated. Test of analysis between two groups was performed using unpaired t-test. We applied correlation technique, that is, Pearson product-moment correlation coefficient (r) to assess the correlation between BIS and SAS. It varies from + 1-0 to -1. Results: Heart rate and blood pressure were more stable and less in Group A than Group B. Duration of mechanical ventilation was found extremely significant between Group A (77.86 ± 5.71 h) and Group B (95.64 ± 17.00 h) (P = 0.001). There was significant difference found in the time of extubation between Group A (21 ± 6.44 h) and Group B (30.4 ± 10.62 h) P = 0.008. Conclusion: It is concluded in this study that sedation with dexmedetomidine resulted in quick extubation and decreased the duration of mechanical ventilation in comparison to midazolam in ICU patients. There was found moderate to high correlation between BIS index and SAS. [ABSTRACT FROM AUTHOR]