Background: Red Blood Cell (RBC) transfusions are commonly used in palliative care. RBCs are a finite resource, transfusions carry risks, and the net effect (benefits and harms) is poorly defined for people with life-limiting illnesses. Objective: To examine the indications and effects of RBC transfusion in palliative care patients. Design: This international, multisite, prospective consecutive cohort study. Setting/Subjects: Palliative care patients undergoing RBC transfusion. Measurements: Target symptoms (fatigue, breathlessness, generalized weakness, or dizziness) were assessed before transfusion and at day 7 by treating clinicians, using National Cancer Center Institute Common Terminology Criteria for Adverse Events. Assessment of harms was made at day 2. Results: One hundred and one transfusions with day 7 follow-up were collected. Median age was 72.0 (interquartile range 61.5-83.0) years, 58% men, and mean Australia-modified Karnofsky Performance Status (AKPS) of 48 (standard deviation [SD] 17). A mean 2.1 (SD 0.6) unit was tranfused. The target symptoms were fatigue (61%), breathlessness (16%), generalized weakness (12%), dizziness (6%), or other (5%). Forty-nine percent of transfusions improved the primary target symptom, and 78% of transfusions improved at least one of the target symptoms. Harms were infrequent and mild. An AKPS of 40%-50% was associated with higher chances of symptomatic benefit in the target symptom; however, no other predictors of response were identified. Conclusions: In the largest prospective consecutive case series to date, clinicians generally reported benefit, with minimal harms. Ongoing work is required to define the optimal patient-and clinician-reported hematological and functional outcome measures to optimize the use of donor blood and to minimize transfusion-Associated risk.