This study aims to assess the feasibility and safety of combined multiple regional anesthesia (CMRA) as a potential strategy to decrease pain and reliance on intravenous analgesics during and after ultrasound-guided microwave ablation (US-guided-MWA) of liver tumors.A cohort of 75 patients with a total of 99 liver tumors who underwent US-guided-MWA of liver tumors were enrolled. These patients were randomly allocated into three groups: A, B, and C. Prior to the ablation procedure, Group A patients received a combination of hepatic hilar block (HHB), Transversus abdominis plane block (TAPB), and local anesthesia (LA). Patients in Group B were administered HHB in conjunction with LA, while those in Group C received TAPB and LA. Evaluative parameters included the Numerical Rating Scale (NRS) scores, consumption of morphine, incidence of complications, and factors influencing perioperative pain.All patients successfully underwent US-guided-MWA. The peak NRS scores for pain during ablation across the three groups were 2.36 ± 1.19, 3.28 ± 1.59, and 4.24 ± 1.42 respectively (P < 0.01), while the count of patients requiring morphine were 4/25, 8/25, and 13/25 respectively (P < 0.01). Postoperative NRS scores for the three groups at 4, 8, 12, 24, and 36-hour intervals demonstrated a pattern of initial increase followed by a decrease, with the order at each interval being: Group A < Group C < Group B. Factors associated with increased pain included larger tumor size, greater number of tumors, and longer procedure and ablation time (P < 0.05). No major complications were recorded across the three groups.CMRA offers an effective and safe modality to manage pain during and after US-guided-MWA of liver tumors.Copyright © 2023 Elsevier B.V. All rights reserved.