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Background There is a high incidence of serious mental illness (SMI) and antipsychotic use in the respiratory high dependence unit (HDU) compared with the general population. However, there is a paucity of data in the extant literature evaluating the relationships between respiratory failure and antipsychotics. Aims To investigate the relationship between antipsychotics and respiratory failure in people admitted to a respiratory HDU, and to gain a better understanding of the potential impact of antipsychotic medications on respiratory outcomes. Method Medical, demographic and clinical outcome data were collected for a consecutive sample of 638 individuals admitted to a respiratory HDU between the dates 1 January 2018 and 29 May 2021 at a large quaternary hospital. Results Multivariate models controlling for confounders found that antipsychotic medications increased risk of admission for type 2 respiratory failure and chronic obstructive pulmonary disease exacerbation without hypercapnia by 3.7 and 11.45 times, respectively. For people admitted with type 2 respiratory failure, antipsychotic use increased the risk of requiring non-invasive ventilation by 4.9 times. Those prescribed an antipsychotic were more likely to be readmitted within 30 days. Over 30% of individuals were prescribed antipsychotics for an unlicensed indication. Conclusions Poor respiratory outcomes may be a previously unknown adverse drug reaction of antipsychotics. Modifications to clinical care and clinical pathways for those with SMI prescribed antipsychotic medications, including optimising their chronic health and deprescribing where appropriate, should be prioritised.