•The high interindividual variability of once-monthly long-acting injectable aripiprazole makes it very difficult to predict its optimal dosing. In this context, population pharmacokinetic models constitute a valuable tool to characterize the pharmacokinetic properties of a drug and quantifying the sources of variability in drug exposure considering factors such as age, gender or genetics, among others. In addition, these models can also be used to optimize dosages in the clinical setting, since they contribute to guide decision-making and improve patient outcomes.•This is the first population pharmacokinetic model developed for LAI aripiprazole that includes aripiprazole and its main active metabolite, dehydroaripiprazole. It provides a personalized dosage recommendation that maximizes the probability of achieving optimal therapeutic concentrations and minimizes the difficulties associated with trial-and-error therapeutic strategies carried out in clinical practice.•Weight was the factor that most influenced aripiprazole absorption, which were inversely correlated. The CYP2D6 metabolizing phenotype and concomitant treatment with strong CYP2D6 inhibitors are the factors that most influence drug elimination and total drug exposure. Population pharmacokinetic (popPK) models constitute a valuable tool for characterizing the pharmacokinetic properties of once-monthly long-acting injectable aripiprazole (LAI aripiprazole) and quantifying the sources of variability in drug exposure. Our aim is to develop a popPK model of both aripiprazole and its metabolite dehydro-aripiprazole in patients treated with LAI aripiprazole, and to personalize the dosing regimen of aripiprazole across different sub-groups of patients. This is a prospective study investigating the pharmacokinetics of LAI aripiprazole. A total of 93 patients were included, 21 for model development and 71 for external model evaluation. A one-compartment model with linear absorption and elimination adequately described both aripiprazole and dehydro-aripiprazole concentrations. The weight of the patients has been shown to be the factor that most influences the absorption. However, the metabolizing phenotype for CYP2D6 and the concomitant treatment with strong inhibitors of this cytochrome have been shown to be the covariates that most influence total drug exposure. This is the first popPK model developed for LAI aripiprazole that includes aripiprazole and its main active metabolite, dehydroaripiprazole. It provides a personalized dosage recommendation that maximizes the probability of achieving optimal therapeutic concentrations and minimizes the difficulties associated with trial-and-error therapeutic strategies carried out in clinical practice.