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Context: Propofol is a general anesthetic used in multiple clinical scenarios. Despite growing evidence supporting its use in palliative care, propofol is rarely used in palliative sedation. Reluctance toward the adoption of propofol as a sedative agent is often associated with fear of adverse events such as respiratory arrest. Objectives: We aimed to describe efficacy and safety of palliative sedation in refractory sedation with propofol using a protocol based on low, incremental dosing. Methods: A retrospective observational study featuring inpatients receiving sedative treatment with propofol in our palliative care unit in Madrid (Spain) between March 1, 2018 and February 28, 2023, following a newly developed protocol. Results: During the study period, 22 patients underwent sedation with propofol. Propofol was used successfully to control different refractory symptoms, mainly psychoexistential suffering and delirium. All patients had undergone previous failed attempts at sedation with other medications (midazolam or lemovepromazine) and presented risk factors for complicated sedation. All patients achieved satisfactory (profound) levels of sedation measured with the Ramsay Sedation Scale, but total doses varied greatly between patients. Most patients (17, 77%) received combined therapy with propofol and other sedative medications to harness synergies. The median time between start of sedation with propofol and death was 26.0 hours. No cases of apnea or death during induction were recorded. Conclusion: A protocol for palliative sedation with propofol based on low, incremental dosing, with the option of administering an initial induction bolus, shows excellent results regarding adequate levels of sedation, without observing apnea or respiratory depression. Our results promote the use of propofol to achieve palliative sedation in patients with refractory symptoms and risk factors for complicated sedation at the end of life. [ABSTRACT FROM AUTHOR]