Background: Red blood cell (RBC) transfusions are commonly prescribed for palliative care patients for symptoms. However, RBCs are a limited resource, transfusion is not without risk, and may be of variable benefit in people approaching the end of life. The aim of this study was to review RBC transfusions in our palliative care unit (PCU), examining evidence of benefit or harms, and preparing for a prospective multisite study. Methods: This consecutive cohort study retrospectively reviewed transfusions administered during a PCU admission. Hemoglobin levels, physical function, and symptom rating for breathing and fatigue (Symptom Assessment Scale) were assessed before transfusion, and at days 2 and 7. Results: Thirty-one patients received 44 transfusions over the two-year period. Of these patients, the average age was 64 years and 45% were male. Eighty-nine percent of transfusions were thought to be of subjective benefit by clinicians, and 94% of patients reported symptomatic improvement. However, overall, there was little change in scale-based measures of physical function or symptoms, with response rates <25% in all scales. No predictors of response were found considering pretransfusion hemoglobin, hemoglobin increment, Australia-modified Karnofsky Performance Status, or discharge status. Deterioration after transfusion was prevalent. Conclusion: For RBC transfusion in palliative care patients, the majority had subjective benefit. However, subjective improvement correlated poorly with objective scale-based measures. The sensitivity of assessment scales, high rates of placebo response, and the multifactorial nature of symptoms at the end of life make evaluation of RBC transfusions challenging.