OBJECTIVES : To estimate the cost-effectiveness of paliperidone palmitate (PLAI), a once-monthly long-acting injectable (LAI) atypical antipsychotic, compared to the most common antipsychotic strategies in France. METHODS: A Markov model was developed to simulate the progression of a cohort of schizophrenic patients through four health states (stable treated, stable non-treated, relapse and death) and up to three lines of treatment. PLAI was compared to risperidone LAI (RLAI), aripiprazole LAI (ALAI), olanzapine LAI (OLAI), haloperidol decanoate (HLAI) and oral olanzapine (OO). Costs, quality-adjusted-life-years (QALYS) and number of relapses were assessed over five years based on three-month cycles, and discounted at 4%, from a health insurance perspective. Patients were supposed to be stabilised after a clinical decompensation and entered the model into an initiation phase, followed by a relapse prevention phase in case of success. In the prevention phase, relapse rates were derived from hospitalisation risks based on French real-life data in order to capture the adherence effects. Safety and utility data were derived from international publications. Costs came from French health insurance databases and publications. Robustness of results was assessed through deterministic and probabilistic sensitivity analyses. RESULTS : PLAI was the less costly LAI and associated with an incremental cost-effectiveness ratio (ICER) of €1,988/QALY gained and €2,267/relapse avoided versus OO. RLAI and PLAI were associated with the highest number of QALYs (ICER of €2,421,386/QALY gained between PLAI and RLAI). PLAI dominated all other LAIs in terms of relapse but OLAI. Nevertheless, PLAI was highly cost-effective versus OLAI (ICER of €1,575,217/relapse avoided). CONCLUSIONS: This analysis is the first to assess the cost-effectiveness of antipsychotics based on French observational data. PLAI was found to be the least expensive LAI antipsychotic from French payer perspective. Oral therapies were less expensive but associated with lower levels of QALYs and more relapses compared to all atypical LAIs.