This study aims to investigate the pharmacokinetics of methotrexate (MTX) in Chinese patients with intracranial germ cell tumors (iGCTs) and to develop a robust population pharmacokinetic (PPK) model. A two-compartment model with an exponential inter-individual variability and a proportional residual model was established using nonlinear mixed-effects modeling. The model was based on 5,470 plasma concentration data points from 505 Chinese iGCT patients, including 370 children. The impact of covariates on model parameters was evaluated using forward addition and backward elimination strategies. Goodness-of-fit plots, bootstrap, visual predictive check and normalized prediction distribution errors were used to assess model performance. In the final model, the clearance of the central compartment (CL) was determined using the following equation