Background and Aims: Opioids are associated with postoperative nausea, vomiting, drowsiness, and increased analgesic requirement. A nonopioid anesthesia technique may reduce morbidity, enable day care surgery, and possibly decrease tumor recurrence. We compared opioid-free, nerve block-based anesthesia with opioid-based general anesthesia for breast cancer surgery in a prospective cohort study. Material and Methods: Twenty four adult American Society of Anesthesiologists grade I–III patients posted for modified radical mastectomy (MRM) with axillary dissection were induced with propofol and maintained on isoflurane (0.8–1.0 minimum alveolar concentration) through i-gel on spontaneous ventilation and administered ultrasound-guided PECS 1 and 2 blocks (0.1% lignocaine + 0.25% bupivacaine + 1 mcg/kg dexmedetomidine, 30 ml). Postoperative nausea, pain scores, nonopioid analgesic requirement over 24 h, stay in the recovery room, and satisfaction of surgeon and patient were studied. Twenty-four patients who underwent MRM and axillary dissection without a nerve block under routine opioid anesthesia with controlled ventilation were the controls. Results: MRM and axillary dissection under the nonopioid technique was adequate in all patients. Time in the recovery room, postoperative nausea, analgesic requirement, and visual analog scale scores were all significantly less in the nonopioid group. Surgeon and patient were satisfied with good patient quality of life on day 7. Conclusion: Nonopioid nerve block technique is adequate and safe for MRM with axillary clearance. Compared to conventional technique, it offers lesser morbidity and may allow for earlier discharge. Larger studies are needed to assess the long-term impact on chronic pain and tumor recurrence by nonopioid techniques.