Background: Surgery and anesthesia are sources of stress to the patients. Inflammatory reactions to this stress have adverse effects on wound healing and remote organs in addition to long-term sequels e.g. adhesion formation. We compared the effects of dexmedetomidine and ketamine on perioperative level of serum inflammatory biomarkers including tumor necrosis factor-α, interleukin-6, and C- reactive protein. Methods: We included Seventy-five patients, aged 30-60, ASA I–II, and scheduled for laparoscopic hysterectomy. Patients were randomized to receive intraoperative ketamine (bolus dose 0.25 mg/kg then continuous infusion 250 µg/kg/h), dexmedetomidine (1µg/kg bolus dose then continuous infusion 0.5 µg/kg/h), or placebo. The primary outcome was to measure serum level of inflammatory biomarkers. Hemodynamic parameters, Recovery time, and complications within 24 hours postoperative were recorded.Results: Whilst there was significant increase in concentrations of inflammatory biomarkers 6 and 24 h postoperative in all groups, there were significant differences between ketamine and dexmedetomidine group as compared to control group with no significant differences between ketamine and dexmedetomidine group. As regard hemodynamic parameters, there were significant increase in ketamine group and decrease in dexmedetomidine group as compared to base line with no need for medical intervention. There was delayed recovery in ketamine group versus control and dexmedetomidine group (24.3 ± 6.4, 12.6 ± 2.0, 13.5 ± 3.3 min respectively; P < 0.001). More complications were reported in ketamine group but did not reach statistical significance. Conclusion: Dexmedetomidine and ketamine are comparable as regards attenuation of perioperative inflammatory response. However, dexmedetomidine has a favorable safety profile.Trial registry number is (PACTR201910617459894: date of registration 10/24/2019)