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AIM & BACKGROUND Non-adherence to antipsychotic treatment is a major issue in the management of severe psychiatric disorders, because it is usually related to future relapses and re-hospitalisations. Long-Acting-Injection (LAI) antipsychotics can be useful to increase treatment adherence in these patients. The aim of the present study was to compare the re-hospitalisation rates of psychotic patients discharged from a psychiatric ward and then, divided into three groups upon the treatment received: LAI antipsychotic, oral antipsychotic at home or oral antipsychotic administered daily by psychiatric nurse staff as patients lived in a long-term care facility. METHODS Data on all inpatients consecutively admitted to the Psychiatric Unit of the Nuovo Ospedale Apuano (Massa, Italy), between January 2017 and December 2018, were obtained by the registration record system. Information about eventual re-hospitalisations of these patients, occurred within a 24-month timeframe since discharge, were collected from the same database. RESULTS In a Kaplan-Meyer analysis, patients treated with LAI antipsychotics showed significantly lower re-hospitalisation rates in the first 24 months after discharge than those treated with oral ones. CONCLUSIONS This study highlights the impact of LAI antipsychotics in preventing re-hospitalisation in severe psychotic patients at high risk in a naturalistic setting. The benefits appear relevant also with respect to a controlled long-term oral antipsychotic treatment, however, further studies are needed to develop more tailored intervention strategies in such complex psychiatric population.