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Background In patients on dialysis with anemia, avoiding red blood cell transfusions is preferable. We sought to develop and validate a novel transfusion prediction risk score for patients receiving maintenance hemodialysis. Methods This retrospective cohort study used United States Renal Data System data to create a model development cohort (patients who were point prevalent and on hemodialysis on November 1, 2012) and a validation cohort (patients who were point prevalent and on hemodialysis on August 1, 2013). We characterized comorbidity, inflammatory conditions, hospitalizations, anemia and anemia management, iron parameters, intravenous iron use, and vitamin D use during a 6-month baseline period to predict subsequent 3-month transfusion risk. We used logistic least absolute shrinkage and selection operator regression. In an exploratory analysis, model results were used to calculate a score to predict 6- and 12-month hospitalization and mortality. Results Variables most predictive of transfusion were prior transfusion, hemoglobin, ferritin, and number of hospital days in the baseline period. The resulting c-statistic in the validation cohort was 0.74, indicating relatively good predictive power. The score was associated with a significantly increased risk of subsequent mortality (hazard ratios 1.0, 1.22, 1.26, 1.54, 1.71, grouped from lowest to highest score), but not with hospitalization. Conclusions We developed a transfusion prediction risk score with good performance characteristics that was associated with mortality. This score could be further developed into a clinically useful application, allowing clinicians to identify patients on hemodialysis most likely to benefit from a timely, proactive anemia treatment approach, with the goal of avoiding red blood cell transfusions and attendant risks of adverse clinical outcomes.