Locked-in syndrome (LIS) is commonly associated with a poor prognosis, particularly if the aetiology is stroke. Dealing with individuals with LIS and a poor prognosis raises the issue of introducing end-of-life discussions with the patient and/or family in the acute period of the illness. Existing literature regarding LIS provides little guidance about end-of-life decision-making in the acute management phase. We aim to provide some guidance for clinicians holding end-of-life discussions in the acute management period. We report two cases of relatively young individuals with LIS secondary to brainstem stroke. Both cases had a very poor prognosis and end-of-life discussions were commenced by the treating team in the acute phase. Despite the severity of their conditions, in neither case were end-of-life discussions well tolerated by the family in the weeks following admission. We suggest that LIS patients and their families, who have chosen to persist with full medical management after diagnosis of LIS, should be provided with sufficient time to adjust to the catastrophic changes that have occurred before further end-of-life discussions are pursued. Education and support are likely to be highly beneficial in the acute period post stroke as they allow the patient and family to develop a realistic understanding of the likely outcomes of their decisions.