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Background: Major depressive disorder (MDD) can have severe impacts on function and quality of life. Up to one third of patients will have an inadequate response to their first line of treatment, with subsequent lines of therapy associated with lower remission rates and higher relapse rates. Recently esketamine has become available for Australian patients, and this agent provides an additional treatment option for those with MDD who have had an inadequate response to two or more antidepressant therapies during the current moderate to severe depressive episode. This paper provides an expert panel's practical recommendations and clinical guidance for establishing esketamine clinics in Australia. Methods: An expert panel (n = 11) comprising psychiatrists, mental health care nurses, pharmacists, and individuals with experience establishing esketamine clinics was convened in Sydney. The panel developed practical recommendations and clinical guidance, which were then further refined. Results: Five key areas were identified: practical considerations for esketamine clinic set‐up, including multidisciplinary care considerations; patient selection; administering esketamine; adverse event management and long‐term follow‐up. Conclusions: Guidance presented in this paper should assist Australian clinicians to set up an esketamine clinic, and provide practical advice on the infrastructure and clinical requirements for treatment of patients with this agent. [ABSTRACT FROM AUTHOR]