Background & Aims: Due to the high prevalence and importance of postoperative pain and opioid complications, we aimed to compare the prophylactic effect of intravenous injection of magnesium sulfate and paracetamol and their combination on pain intensity after Deep Vitrectomy in this study. Materials & Methods: In this clinical trial study, 140 candidates of Deep Vitrectomy randomly distributed in four groups of 35. in the first group, 7. 5 mg/kg magnesium sulfate was injected 20 minutes before the operation. In the second group, 15 mg/kg paracetamol, in the third group 10 mg/kg paracetamol plus 5 mg/kg magnesium sulfate within ten minutes, and in the fourth group, normal saline with the same volume was injected. The patients were then examined and compared in terms of hemodynamic parameters, pain intensity, amount of palliatives consumed, frequency of receiving palliatives, and occurrence of postoperative complications. Results: The mean postoperative pain intensity in the four groups of magnesium sulfate, paracetamol, magnesium sulfate-paracetamol, and control were 1. 32 ±,0. 9, 1. 42 ±,0. 34, 1. 05 ±,0. 38, and 1. 72 ±,0. 95, respectively, and the difference between the groups was significant (P = 0. 003). The number of patients received pethidine were significantly lower in the combination group than the other groups (P = 0. 018). The time interval between entering recovery and receiving analgesia in the group was significantly longer in the combination group than the other groups (P <0. 001). Conclusion: The use of magnesium sulfate-paracetamol combination reduces the postoperative pain intensity, prolongs the time of requesting analgesia, and reduces the use of analgesia within 24 hours after surgery, without any significant hemodynamic complication.