Background: Ropivacaine is commonly used in local infiltration anaesthesia (LIA) as pain management after total knee arthroplasty (TKA). Although considered safe, no studies evaluated the pharmacokinetics of high-dose ropivacaine infiltration in simultaneous bilateral TKA. Methods: We studied 13 patients undergoing unilateral and 15 undergoing bilateral TKA. Standard LIA technique was used with ropivacaine 0.2%, 200 ml (400 mg) injected peri-articularly in each knee. Free and total plasma concentrations of ropivacaine were measured within 24 h using liquid chromatography–mass spectrometry. A population pharmacokinetic model was built using non-linear mixed-effects models. Results: Peak free ropivacaine concentration was 0.030 (0.017–0.071) μg ml⁻¹ (mean [99% confidence interval]) vs 0.095 (0.047–0.208) μg ml⁻¹, and peak total ropivacaine concentration was 0.756 (0.065–1.222) μg ml⁻¹ vs 1.695 (0.077–3.005) μg ml⁻¹ for unilateral and bilateral TKA, respectively. The pharmacokinetics was ascribed a one-compartment model with first-order absorption. The main identified covariates were protein binding, allometrically scaled body weight on clearance and volume, and unilateral or bilateral surgery on volume. Conclusions: This is the first study to investigate the pharmacokinetics of free and total ropivacaine after unilateral and bilateral TKA. A population model was successfully built and peak free ropivacaine concentration stayed below previously proposed toxic thresholds in patients undergoing unilateral and bilateral TKA receiving LIA with high-dose ropivacaine. Clinical trial registration: ClinicalTrials.gov Identifier: NCT04702282