The intra- and inter-individual variances of methotrexate (MTX) pharmacokinetics are extremely large, and the pharmacokinetic property of MTX in patients with primary central nervous system lymphoma (PCNSL) is unestablished. A total of 701 MTX plasma concentrations from 98 patients with PCNSL under high-dose MTX therapy were used to develop the population pharmacokinetic (popPK) model of MTX by using the nonlinear mixed-effects modeling method. A 2-compartment model was employed to describe the pharmacokinetic property of MTX. In the final popPK model, inclusion of serum creatinine and body surface area significantly reduced objective function value for clearance over the base model (p < 0.001), and inclusion of age significantly reduced objective function value for distribution volume of central compartment (V-c) over the base model (p < 0.001). In the final popPK model, the inter-individual clearance = 6.67 x (SCR/68.1)(-0.48) x (BSA/1.75)(1.17); V-c = 24.46 x (age/57.16)(0.81). The precision of all parameters was acceptable (relative standard error < 28.61%). Bootstrap and visual predictive check results indicated that the final popPK model was stable with acceptable predictive ability. The popPK model may be useful for personalized medication in PCNSL patients under high-dose MTX therapy. Further studies are warranted to confirm the results. (C) 2018 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.