BACKGROUND Patients with anemia and lower-risk myelodysplastic syndromes in whom erythropoiesis-stimulating agent therapy is not effective generally become dependent on red-cell transfusions. Luspatercept, a recombinant fusion protein that binds transforming growth factor β superfamily ligands to reduce SMAD2 and SMAD3 signaling, showed promising results in a phase 2 study. METHODS In a double-blind, placebo-controlled, phase 3 trial, we randomly assigned patients with very-low-risk, low-risk, or intermediate-risk myelodysplastic syndromes (defined according to the Revised International Prognostic Scoring System) with ring sideroblasts who had been receiving regular red-cell transfusions to receive either luspatercept (at a dose of 1.0 up to 1.75 mg per kilogram of body weight) or placebo, administered subcutaneously every 3 weeks. The primary end point was transfusion independence for 8 weeks or longer during weeks 1 through 24, and the key secondary end point was transfusion independence for 12 weeks or longer, assessed during both weeks 1 through 24 and weeks 1 through 48. RESULTS Of the 229 patients enrolled, 153 were randomly assigned to receive luspatercept and 76 to receive placebo; the baseline characteristics of the patients were balanced. Transfusion independence for 8 weeks or longer was observed in 38% of the patients in the luspatercept group, as compared with 13% of those in the placebo group (P<0.001). A higher percentage of patients in the luspatercept group than in the placebo group met the key secondary end point (28% vs. 8% for weeks 1 through 24, and 33% vs. 12% for weeks 1 through 48; P<0.001 for both comparisons). The most common luspatercept-associated adverse events (of any grade) included fatigue, diarrhea, asthenia, nausea, and dizziness. The incidence of adverse events decreased over time. CONCLUSIONS Luspatercept reduced the severity of anemia in patients with lower-risk myelodysplastic syndromes with ring sideroblasts who had been receiving regular red-cell transfusions and who had disease that was refractory to or unlikely to respond to erythropoiesis-stimulating agents or who had discontinued such agents owing to an adverse event.