•Liver resection surgery is associated with substantial postoperative pain.•Subcostal transversus abdominis plane block is the suggested regional block.•Erector spinae plane block reduced opioid consumption.•Erector spinae plane block prolonged the duration of analgesia. The aim of this study was to compare the analgesic efficacy of erector spinae plane block (ESPB) in relation to subcostal transversus abdominis plane block (TAPB) in patients undergoing open liver resection surgery. In this randomized controlled trial, we included adult patients undergoing open liver resection surgery. After induction of general anaesthesia, the included patients were randomized to receive either ESPB (n = 30) or subcostal TAPB (n = 30). Postoperative pain was assessed using the numeric rating scale (NRS) at rest and during cough. Intravenous morphine boluses were used for management of breakthrough pain intra- and postoperatively. The study’s primary outcome was morphine consumption during the first 24 h postoperatively. Secondary outcomes included intraoperative morphine consumption, time to first postoperative morphine requirement, incidence of complications, and patient satisfaction. Sixty patients were included and were available for the final analysis in this study. The intra-and postoperative morphine consumption were less in the ESPB group than the subcostal TAPB group (median quartiles morphine dose: 0 0−0 vs 2 0−5 mg, p = 0.007 and 20 15–20 vs 25 20−30 mg, p = 0.006, respectively). The time to first morphine requirement was longer in the ESPB group (median quartiles: 6.5 5.5−6.5 h) than the subcostal TAPB group (median quartiles: 4.3 1.0−6.5 h), P = 0.013. Patients in the ESPB group had lower incidence of sedation and higher level of satisfaction than the subcostal TAPB group. In patients undergoing open liver resection surgery, ESPB provided superior analgesic properties than subcostal TAPB. Clinical trial registration: NCT05253079, Principal investigator: Maha Mostafa, Date of registration: February 23, 2022. URL: https://clinicaltrials.gov/ct2/show/NCT05253079