OBJECTIVES: Achieving treatment continuity to antipsychotic therapy in schizophrenia is a major challenge, though results in a significant reduction of the relapse risk. The 3-monthly long-acting therapy of paliperidone palmitate (PP3M), a novel treatment for schizophrenia, results in the longest dosing interval available while having the same active ingredient as the existing 1-monthly long-acting therapy (PP1M). This study assessed the cost-effectiveness of PP3M versus the PP1M in patients with schizophrenia using a cost-utility model. METHODS: A Markov model with monthly cycles was developed. The model encompassed three lines of therapies with PP3M or PP1M in the first-line, no active treatment in the second-line, and follow-up treatment reflecting current Belgian practice in the third-line. On each line of therapy, patients could be in stable disease, experience relapse (event), experience temporary adverse events (AEs) or permanent AEs (health states), or die. Patients who discontinued their treatment were switched to the subsequent treatment until the end of the model or death. Relapse rates were based on the pivotal non-inferiority head-to-head trial, and treatment discontinuation of PP3M and PP1M was based on Belgian real-world evidence. A time dependent relapse rate was applied for the first 8 months of no treatment following on the discontinuation of PP1M or PP3M to account for differences in drug exposure. The adopted perspective was that of the Belgian healthcare payer over a 5-year time horizon. Costs and effects were discounted at an annual rate of 3% and 1.5%, respectively. One-way and probabilistic sensitivity analyses were performed to assess parameter variability on model outputs. RESULTS: PP3M dominates PP1M resulting in lower costs (€ 1,211) and more QALYs (0.10). Sensitivity analyses indicated that the results were robust to key parameter variation. CONCLUSIONS: PP3M reduces the costs while increasing the QALYs due to a better treatment continuation resulting in less relapses and decreased hospitalization costs.