Background: Cancer breast is the commonest cancer affecting females and mastectomy is still the standard therapy. However, uncontrolled intraoperative (IO) and postoperative (PO) pain will progress for long-term and affects patients' quality of life (QOL). Objectives: The effect of perioperative dexmedetomidine (DEX) and Ketamine/Midazolam (KET/MID) infusions on the incidence and severity of postmastectomy pain (PMP) and patients' QOL. Patients & Methods: 120 women were randomly divided into Placebo, K/M and DEX groups. Bolus dose (0.5 ml/kg) was given over 10-min before induction, followed by IO and PO infusions at rate of 0.25 and 0.1 ml/ kg/h, respectively. PMP was evaluated at time of discharge and two monthly for 6-m PO for pain sensation with assessment of the neuropathic character of pain using Douleur Neuropathique-4 questionnaire. Patients' QOL at the 6th month PO was evaluated using the Short-form questionnaire and surgeon's satisfaction was evaluated using 5-point scale. Results: incidence of PMP was 55%, 35% and 22.5% in placebo, K/M and DEX groups, respectively. Median PMP score was significantly lower with DEX than other infusions and with K/M than Placebo infusion. Neuropathic pain scoring was significantly higher with placebo than other infusion. Patients' QOL and surgeon's satisfaction scorings were significantly higher with DEX and K/M infusions than Placebo infusion and with K/M infusion than Placebo infusion. Conclusion: Perioperative DEX or KET infusion significantly reduced the incidence and severity of PMP with improvement of patients' QOL and surgeon's satisfaction. DEX perioperative infusion provided superior outcome than K/M infusion.