ABSTRACT Background: Percutaneous radiofrequency ablation (PRFA) of hepatic tumors is a painful procedure. Regional anesthesia is currently considered one of the fundamental elements for managing both intra and postoperative pain. We aimed to compare the analgesic efficacy of ultrasound-guided erector spinae plane block (ESPB) versus local anesthetic infiltration for pain relief in patients undergoing PRFA of liver tumors. Methods: Sixty adult patients undergoing PRFA of primary or secondary liver malignancies were randomized into: Group I (local anesthetic infiltration group) or Group II (right ultrasound-guided ESPB group). Postoperative pain score as a primary outcome, rescue analgesic consumption, number of subjects requiring general anesthesia and incidence of complications were recorded. Results: Postoperative pain score was significantly lower in Group II during the first 4 hours postoperatively (P = 0.000*, 0.000*, 0.001*, 0.001* and 0.002*, respectively) as compared to Group I, whereas comparable pain scores were recorded among the study groups at 8, 12, 16, and 24 hours postoperative (P = 0.492, 0.075, 0.893, and 0.094, respectively). Intra and postoperative rescue analgesic requirement was significantly less in Group II than Group I (P = 0.031*, and 0.000*, respectively). Nine patients in Group I and two patients in Group II were converted to general anesthesia. The incidence of adverse events was comparable between the two groups. Conclusions: Ultrasound-guided ESPB provided efficient analgesia during intraoperative and early postoperative periods with reduced analgesic requirements and fewer patients needing general anesthesia as compared to local infiltration technique. Trial registry: Pan African Clinical Trials Registry (PACTR201705002296409).