BACKGROUND Long-acting injectable (LAI) antipsychotics are used as a monotherapy in patients with schizophrenia. However, the combination of LAI and oral antipsychotics is commonly used in clinical practice, despite there being very limited studies investigating the efficacy and safety of this combination compared with LAI antipsychotic monotherapy. OBJECTIVE To study the efficacy and safety of LAI antipsychotic monotherapy compared with the combination of LAI and oral antipsychotics in patients with schizophrenia. METHODS This study was a retrospective cohort study, which classified eligible patients into two groups: the LAI antipsychotic monotherapy group and the combination of LAI and oral antipsychotic group. The primary outcome was hospitalization between groups. The duration of the study was 2 years. RESULTS In total, 86 patients completed the study and were analysed (LAI antipsychotic monotherapy group: n = 25; combination of LAI and oral antipsychotic group: n = 61). There was no significant difference in hospitalization between the two groups (P = 1.000). For other outcomes, there were also no significant differences in both all-cause discontinuation (P = 0.667) and adverse drug reactions (P = 0.732) between the two groups. CONCLUSIONS The efficacy and safety of LAI antipsychotic monotherapy appeared similar to the combination of LAI and oral antipsychotics in patients with schizophrenia. Therefore, the combination of LAI and oral antipsychotics, which is commonly used in clinical practice, may not be necessary.