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Introduction: Dexmedetomidine is a potent and highly selective alpha-2 adrenoreceptor agonist with the unique sedative, analgesic, perioperative sympatholytic, anaesthetic-sparing and haemodynamic-stabilizing properties. Fentanyl is a potent, synthetic opioid pain medication with a rapid onset and short duration of action. Aim: To examine the effects of fentanyl and dexmedetomidine with paracetamol administered by intravenous route on the postoperative Interleukin (IL-6) and C-reactive protein (CRP) response in oral cancer surgery. Materials and Methods: This prospective comparative study included 60 patient of American Society of Anaesthesiologists (ASA) grade I or II, aged 18 to 70 years. 60 patients were divided into two groups: Group A- Paracetamol (10 mg/kg) with fentanyl (2 µg/kg), maintenance with fentanyl (3 µg/kg); and Group BParacetamol (10 mg/kg) with dexmedetomidine (0.5 µg/kg), maintenance with dexmedetomidine (0.4 µg/kg). Blood samples were collected before induction at the end of surgery and 24 hours after surgery for serum level of CRP and IL-6. Results: The demographic profiles such as age, weight, duration of surgery, ASA grade and tumour stage were similar in both groups. CRP and IL-6 level were significantly lower in groups postoperatively at 24 hours as compared to preoperatively and immediate postoperatively. The Visual Analogue Scale (VAS) score and rescue analgesic for 24 hour were lower in group B than group A. Conclusion: Dexmedetomidine is an effective drug which reduces requirement of opioid and potentially increases the analgesia. Adverse effects were not significantly different between the groups.