Background: Breast surgery is an exceedingly common procedure with an increased incidence of acute and chronic pain. Pectoral nerve block is a novel peripheral nerve block alternative to neuro-axial and paravertebral blocks for ambulatory breast surgeries. Objectives: This study aims to compare the analgesic efficacy and safety of modified Pecs block with ketamine plus bupivacaine versus bupivacaine in patients undergoing breast cancer surgery. Study Design: A randomized, double-blind, prospective study. Setting: Academic medical center. Methods: This study is registered at www.clinicaltrials.gov under number: (NCT02620371) after approval by the ethics committee of South Egypt Cancer Institute, Assuit University, Assuit, Egypt. Sixty patients aged 18 – 60 years scheduled for modified radical mastectomy were enrolled and randomly assigned into 2 groups (30 patients each): Control group patients were given ultrasound-guided, Pecs block with 30 mL of 0.25% bupivacaine only. Ketamine group patients were given ultrasound-guided, Pecs block with 30 mL of 0.25% bupivacaine plus ketamine hydrochloride (1 mg/kg). Patients were followed up for 48 hours postoperatively for vital signs, VAS score, first request of rescue analgesia and total morphine consumption, sedation score, and side effects. Results: Ketamine plus bupivacaine in Pecs block compared to bupivacaine alone prolonged the mean time of first request of analgesia (18.25 ± 1.98), (12.56 ± 2.64), respectively (P 0.001), reduced total morphine consumption (12.50 ± 4.63), (18.86 ± 6.28), respectively (P = 0.016). With no significant difference in hemodynamics, respiratory rate, oxygen saturation, VAS and sedation scores, and side effects observed between the 2 groups (P > 0.05). Limitations: This study is limited by its sample size. Conclusion: The addition of ketamine to modified Pecs block prolonged the time to first request of analgesia and reduced total opioid consumption without serious side effects in patients who underwent a modified radical mastectomy.