Background: Modified radical mastectomy (MRM) with axillary clearance of lymph nodes was routinely performed under general anaesthesia with intra-and postoperative opioid analgesia. Recently, there has been a move toward opioid-free anesthesia (OFA) to appreciate the goals of hypnosis with amnesia and sympathetic stability without the adverse effects of opioids.The aim of this study was to evaluate the effect of OFA versus opioid-based anaesthesia (OBA) in patients with breast cancer, who had undergone unilateral MRM. The primary aims:• Pain intensity using the visual analogue scale in the first 24 h post-operatively.• Screening for post mastectomy neuropathic pain. The secondary aims:• Effect of opioid and surgical stress on the immune system.• Patient outcome including haemodynamic stability, patient satisfaction and occurrence of post-operative complications. Methods: Forty adult female patients scheduled for elective unilateral MRM were randomly divided into two groups (20 patients in each group): OFA and OBA. Results: There was statistically significant decrease in pain score at rest and on movement in the OFA group. Postoperative nausea and vomiting was significantly decreased in the OFA group (P = 0.04). Patients in the OFA group were more satisfied than those in the OBA group using verbal rating scale for satisfaction (P < 0.001). There was significant low incidence of neuropathic pain in the OFA group; also, we found significant changes in interleukin 10, tumour necrosis factor alpha and caspase 3 between the two groups. Conclusion: OFA is safe and effective in mastectomy as it decreases the pain score and the incidence of post mastectomy neuropathic pain; moreover, it also shows better immune response postoperatively.