Pectoralis and serratus plane blocks (Pecs-II block) has successfully demonstrated a good quality of perioperative analgesia for breast surgery. This study aimed to compare the quality of postoperative pain control when adding either ketamine or dexmedetomidine to bupivacaine 0.25% for Pecs-II block. This prospective randomized double-blind study was conducted on 159 female patients with American Society of Anesthesiologist (ASA) physical status class I-III scheduled to have modified radical mastectomy. Patients were randomly assigned into 3 groups. Each group included 53 patients to receive ultrasound guided Pecs-II blocks with either 32mL of 0.25% bupivacaine added to ketamine hydrochloride 1mg/kg (BK group), 32mL of 0.25% bupivacaine added to dexmedetomidine 1ug/kg (BD group) or 32mL of 0.25% bupivacaine only (B group).The primary outcome was the total postoperative morphine consumption for the first 24 hours postoperatively. The time of the first request of analgesia, the pain scores at rest of ipsilateral arm, and the intraoperative fentanyl requirements, were the secondary outcome measures. Any side effects occurred were recorded. The total postoperative morphine consumption was significantly lower in patients received bupivacaine with addition of either ketamine (BK group), (10.3±2.6mg), or dexmedetomidine (BD group), (3.8±0.2mg) respectively, versus patients received only bupivacaine (B group), (16.9±5.3mg). Both ketamine (BK group) and dexmedetomidine (BD group) added to bupivacaine significantly prolonged the time to first analgesic request (16.7±4.5h), (21.6±1.6h) in both groups respectively compared with patients received bupivacaine alone (B group) (11.5±1.2h).The pain score was variable between the 3 groups during the first 24 hours postoperatively. There were no statistically significant differences in perioperative hemodynamics, O 2 saturation, sedation scores, or side effects observed between the 3 groups. Patient satisfaction was reported to be the best in patients received dexmedetomidine added to bupivacaine compared to the patients who received ketamine as an additive or those who received bupivacaine alone. Adding dexmedetomidine to bupivacaine provides more effective postoperative pain control than adding ketamine during Pecs-II blocks for breast cancer surgery.