To develop a population pharmacokinetic (PK) model for risperidone ISM® and to investigate relationships between active moiety exposure, as described by apparent clearance (CL40), and several covariates using all data from five clinical studies. A population PK model was developed using active moiety concentrations from a study in healthy volunteers and two studies in patients with schizophrenia. Data from a comparative bioavailability study in medically stable patients and a Phase III study in patients with acute exacerbation of schizophrenia were then incorporated, using empirical Bayesian feedback and model refinement in NONMEM. Finally, covariate analysis was performed on CL40. The final model adequately described the pharmacokinetics of 6288 active moiety concentrations in 17 healthy volunteers and 430 patients with schizophrenia. This one-compartment disposition model had a complex absorption process, combining a small amount immediately entering the central active moiety compartment, two first-order absorption processes and a combined zero-order and first order process, with first-order elimination from the central compartment. Significant covariates on CL40 were BMI and sex. Goodness of fit (GOF) plots and visual-predictive checks (VPC) confirmed acceptable description of the data. The population PK model adequately described active moiety concentrations from five clinical studies after risperidone ISM® administration. Relationships between active moiety exposure and covariates were defined to facilitate simulations for future studies. The model showed that risperidone ISM® rapidly achieves therapeutic plasma levels within first hours after the first injection that are maintained sustainedly throughout the whole dosing interval following once-monthly gluteal injections for 100 mg and 75 mg.