BackgroundAnemia in myelodysplastic syndromes (MDS) is associated with poorer health‐related quality of life (HRQoL) and physical function, and is frequently treated with transfusions. The current common practice of transfusing multiple red blood cells (RBC) units every 2–4 weeks may result in peaks/troughs in hemoglobin (Hb) level, yet maintaining a stable Hb may better improve HRQoL. We describe a study protocol aiming to investigate the feasibility of weekly low‐dose RBC transfusion in MDS patients, including assessing HRQoL and physical function outcomes.Study Design and MethodsIn this n‐of‐1 pilot study, patients receive two treatment arms, with randomly allocated treatment sequence: arm A (patient's usual transfusion schedule) and arm B (weekly transfusion, individualized per patient). To facilitate timely delivery of weekly transfusion, extended‐matched RBCs are provided, with transfusion based upon the previous week's Hb/pre‐transfusion testing results to eliminate delays of awaiting contemporaneous cross‐matching. Primary outcome is the feasibility of delivering weekly transfusion. Secondary outcomes include HRQoL, functional activity measurements, RBC usage, and alloimmunization rates. A qualitative substudy explores patient and staff experiences.ResultsThe trial is open in Australia, Netherlands, and UK. The first patient was recruited in 2020. Inter‐country differences in providing RBCs are observed, including patient genotyping versus serological phenotyping to select compatible units.DiscussionThis pilot trial evaluates a novel personalized transfusion approach of weekly matched RBC transfusion and challenges the dogma of current routine pre‐transfusion matching practice. Findings on study feasibility, HRQoL, and physical functional outcomes and the qualitative substudy will inform the design of a larger definitive trial powered for clinical outcomes.