Background and Objectives: Postoperative pain and stress elicit hormonal changes. We aimed at comparing the effects of wound infiltration with ketamine versus dexmedetomidine on postoperative pain and stress response. Methods: This double-blinded study included ninety patients scheduled for total abdominal hysterectomy and were randomly assigned into three groups to receive local wound infiltration with 40 mL of 0.25% bupivacaine (group C), plus 2 mg/kg ketamine (group K) or 2 lg/kg dexmedetomidine (group D). Primary outcome was postoperative morphine consumption; secondary outcomes included first request of analgesia, VAS scores at rest and movement (VAS–R/M) and side effects. Serum cortisol, prolactin and glucose levels at baseline, pre-infiltration, 6 and 24 h postoperatively were measured. Results: Rescue analgesia was less in K (6.80
3.19 mg) and D (8.39
3.86 mg) compared to C (13.33
4.01 mg) (p 0.05). First request of analgesia was delayed in K (7.60
4.16 h) and D (6.00
3.73 h) compared to C (4.20
1.13 h) (p 0.05). Both VAS and R/M were significantly lower in K (all over 24 h) and D (for 8 and 4 h, respectively) compared to C. Stress markers were significantly lower in K and D compared to C at 6 and 24 h, and in K compared to D at 24 h (p 0.05). Conclusions: Local wound infiltration with ketamine or dexmedetomidine added to bupivacaine had an opioid-sparing effect, delayed first request of rescue analgesia, and attenuated postoperative stress response, especially with ketamine in patients underwent total abdominal hysterectomy.