OBJECTIVES: Aripiprazole once-monthly (AOM) is a long-acting injectable formulation of aripiprazole, and is approved in Europe for the maintenance treatment of schizophrenia after stabilization with oral aripiprazole. The objective of this research was to evaluate the cost-effectiveness of AOM versus paliperidone palmitate (PP) in the maintenance treatment of schizophrenia in Spain. METHODS: This pharmacoeconomic evaluation was conducted alongside a 28-week, randomized, open-label, rater-blinded study comparing AOM 400mg and PP (50-150mg) in stabilized adults with schizophrenia. Effectiveness outcomes of the cost-effectiveness analyses (CEA) included the changes in Heinrichs-Carpenter Quality of Life Scale (QLS-primary CEA) and Clinical Global Impression-Severity (CGI-S) score at week 28. Visits with healthcare providers, out- and in-patient services were collected using a health economic assessment questionnaire (HEA). Healthcare services unit costs from the Basque Country were used (2014 costs). All patients with at least one valid post-baseline HEA were eligible for analysis. Bootstrapped confidence intervals were generated from 10,000 simulations, as well as cost-effectiveness acceptability curves. RESULTS: Over the total 28-week period, AOM was associated with significantly reduced total healthcare costs compared to PP (mean per-patient cost: €1,935 vs. €2,475, respectively; p<0.001). This cost reduction was primarily due to significant reduction in drug acquisition costs (€1,237 vs. €1,889; p<0.001). The other cost aggregates (healthcare provider costs, out- and in-patient costs) were not statistically different between drugs (p=0.528, p=0.102 and p=0.194, respectively). In the primary CEA, AOM dominated PP (being more effective on the QLS scale and less costly). This result was confirmed when using CGI-S as effectiveness measure. The cost-effectiveness acceptability curves indicated that AOM was the treatment of choice whatever willingness-to-pay threshold used. CONCLUSIONS: Aripiprazole once-monthly was associated with statistically significantly reduced healthcare costs and greater effectiveness compared to paliperidone palmitate in all scenarios, showing its economic value in the management of maintenance schizophrenia in Spain.