OBJECTIVES Schizophrenia is a heterogeneous chronic disease with enormous economic consequences for the society. This study aimed at building a conceptual framework to evaluate the cost-effectiveness of Aripiprazole Once-Monthly (AOM) versus other atypical long-acting injectable (LAI) antipsychotics: Risperidone LAI (RLAI), Paliperidone Palmitate (PP) and Olanzapine Pamoate (OP) in the maintenance treatment of schizophrenia.  METHODS The schizophrenia Markov model developed by the National Institute for Health and Care Excellence (NICE) was adapted to the context of LAI antipsychotics. Effectiveness was measured through Quality-Adjusted Life Years (QALYs) and number of relapses. The economic analysis was conducted over a ten-year time horizon, including cost of managing stable schizophrenia, relapse and treatment-emergent adverse events (TEAEs). Probabilities of relapse, discontinuation due to adverse events, and due to other reasons came from a mixed treatment comparison of pivotal clinical trials; disutilities associated to TEAEs and other non-drug-specific inputs came from various epidemiological sources. RESULTS AOM was associated with higher number of QALYs (7.26 vs 7.17, 7.18 & 7.19 for PP, RLAI and OP respectively) over a 10-year time horizon. Assuming a theoretical parity price between AOM and PP, the base case analysis showed that AOM was the dominant strategy as compared to RLAI, PP and OP. Deterministic sensitivity analyses confirmed these overall conclusions, the main drivers of cost-effectiveness being both probability and cost of relapse. In the probabilistic sensitivity analysis, AOM demonstrated a higher probability of being cost-effectiveness than RLAI, PP and OP at a willingness to pay threshold of £20,000 (52%, 89% and 90%, respectively). CONCLUSIONS Although model outcome may vary according to local data and settings, and assuming a theoretical parity price with PP, AOM was found to provide clinical benefits at lower total costs compared to other atypical LAI antipsychotics, showing its value in the maintenance treatment of schizophrenia.