Introduction: Although it is known that antipsychotic non-compliance increases the risk of emergency department (ED) utilisation, presentation with agitation/aggression and rehospitalisation in schizophrenia spectrum disorders (SSD) patients, it is unwell known whether antipsychotic monotherapy vs. polypharmacy differs in terms of efficacy in these domains. This study aimed to determine the effectiveness of antipsychotic monotherapy and polypharmacy for the prevention of hospitalisation who admitted to the ED in the real-world. Methods: The study was conducted with electronic health records of 669 SSD patients admitted to the ED between 2019 and 2022. Patients were evaluated in four groups according to antipsychotic use at the first admission to the ED: antipsychotic non-compliance for more than 90 days, antipsychotic non-compliance for 15-90 days, antipsychotic monotherapy and polypharmacy. All antipsychotics and other psychotropic drugs used by the patients were also recorded and followed up for at least one year after index admission. Results: The groups, including patients with antipsychotic non-compliance, had higher ED visits, more hospitalisations and more admissions with agitation/aggression compared to antipsychotic monotherapy or polypharmacy. However, no differences were found between monotherapy and polypharmacy groups regarding these outcomes. Patients discharged with monotherapy or polypharmacy also had similar re-hospitalisation rates at follow-up. Conclusions: There is no positive evidence that recommending polypharmacy over antipsychotic monotherapy is superior in the frequency of ED visits, ED admissions with agitation/aggression, hospitalisation and re-hospitalisation. In this context, it may be more feasible to clozapine monotherapy before antipsychotic polypharmacy in treatment-resistant patients due to more significant evidence.