The purpose of this study was to explore the pharmacokinetics (PK) characteristics and safety of continuous lidocaine infusion during hepatectomy in liver cancer patients.This study included thirty-five patients undergoing laparoscopic hepatectomy from January 2021 to December 2021. Patients received a short infusion of 1% lidocaine at a dose of 1.5 mg/kg based on ideal body weight, followed by a continuous infusion of 1 mg/kg/h during the operation. The plasma concentrations of lidocaine and its active metabolites were measured using validated ultra-performance liquid chromatography-tandem mass spectrometry. Safety was evaluated by monitoring and recording all adverse events (AEs).The concentrations of lidocaine were within the safe range, except one patient's concentration of lidocaine which reached the toxic range (> 5 μg/mL). The mean half-life (T1/2), the mean time to maximum observed concentration (Tmax), and the mean maximum observed concentration (Cmax) of lidocaine were 3.96 h, 2.85 h, and 2030 ng/mL, respectively; the mean T1/2, Tmax, and Cmax (n = 32) of MEGX were 6.59 h, 5.05 h, and 333.28 ng/mL, respectively; and the mean T1/2, Tmax, and Cmax of GX (n = 18) were 25.98 h, 7.33 h, and 75.81 ng/mL. Although eight subjects with AEs were reported, there were no serious AEs or deaths. No patients had serious postoperative complications. No deaths occurred within 30 days after the operation.Under the administration regimen of this study, intravenous infusion of lidocaine is safe and tolerable for liver cancer patients with laparoscopic hepatectomy. Fine safety and PK characteristics support the application of lidocaine in such patients and further clinical research.China Clinical Trial Registration Center (ChiCTR2100042730), Registered 27 January 2021.© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.