Background: The erector spinae plane block is a newer technique of analgesia to the chest wall. Objective: The study was carried out to establish the efficacy and safety of this block in patients undergoing total mastectomy and axillary clearance. Design: Prospective randomized controlled study. Setting: Single tertiary care center, the study was conducted over a period of 1 year. Patients: 65 patients were included; final analysis was done for 60 female patients undergoing total mastectomy and axillary clearance under general anesthesia were randomly allocated to two groups. Intervention: Group B (block group) received ultrasound-guided erector spinae plane block at T5 level with ropivacaine (0.5%, 0.4 mL/kg) while the control group did not receive any intervention. Postoperatively, patients in both groups received morphine via intravenous patient-controlled analgesia device. Patients were followed up for 24 h postoperatively. Main Outcome Measures: The 24-hour morphine consumption was considered as the primary outcome and secondary outcomes included time to first rescue analgesia, pain scores at 0, ½, 1, 2, 4, 6, 8, 12, and 24 h and characteristics and complications associated with block procedure. Results: The 24-hour morphine consumption was 42% lower in block group compared to control group [mean (SD), 2.9 (2.5) mg vs 5.0 (2.1) mg in group B and group C, respectively, P = 0.01]. The postoperative pain score was lower in group B vs group C at 0, 1/2, 1, 2, 4, 6, 12, and 24 h (P < 0.05). 26 patients in group C against 14 in group B used rescue analgesia within 1 h of surgery (P = 0.01). Conclusion: Erector spinae block may prove to be a safe and reliable technique of analgesia for breast surgery. Further studies comparing this technique with other regional techniques are required to identify the most appropriate technique.