Background To investigate the effect and drawbacks of different LA volumes and concentrations of ESPB on postoperative need for opioids and rescue analgesics, post-mastectomy acute neuropathic pain, and NK cells cytotoxicity.Methods 60 breast cancer patients, ranging in age from 18 to 70 and with an ASA I–II, were randomly assigned to receive ESPB with 20 ml 0.25% bupivacaine (Standard volume ESPB), 40 ml 0.125% bupivacaine (High volume ESPB), or no ESPB (GA only group) after being scheduled for surgery. The primary outcome was total morphine administered over the first 24 postoperative hours. The secondary endpoints were amount of rescue analgesia needed, acute neuropathic pain assessed by DN4 questionnaire, NKC cytotoxicity and complications.Results Total amount of morphine consumed was less in both ESPB groups compared with the control (1.13 ± 1.77 vs. 1.35 ± 3.15 vs. 9.58 ± 5.76, p