Linezolid is a valuable therapeutic option for infections of the central nervous system caused by multi-drug resistant Gram-positive pathogens. Data regarding linezolid pharmacokinetics in cerebrospinal fluid from post-operative neurosurgical patients have revealed wide inter-individual variability. The objectives of this study were to establish a population pharmacokinetic model for linezolid in plasma and cerebrospinal fluid, as well as to optimize dosing strategies in this susceptible population.This was a prospective pharmacokinetic study in post-operative neurosurgical patients receiving intravenous linezolid. Parallel blood and cerebrospinal fluid samples were collected and analyzed. The population pharmacokinetic modelling and Monte Carlo simulations were performed using the Phoenix NLME software.A two-compartment model (central plasma and cerebrospinal fluid compartments) fit the linezolid data well, with creatinine clearance and serum procalcitonin as significant variables. Linezolid demonstrated highly variable penetration into cerebrospinal fluid, with a mean cerebrospinal fluid/plasma ratio of 0.53. A strong correlation was found between plasma trough concentration and cerebrospinal fluid exposure of linezolid. Based on simulation results, optimal dosage regimens stratified by various renal functions and inflammatory status were proposed.A modeling and simulating strategy was employed in dose individualization to improve the efficacy and safety of linezolid treatment.Copyright © 2022. Published by Elsevier Inc.