<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>In the absence of randomized, controlled trial data to support iron chelation therapy in transfusion‐dependent patients with myelodysplastic syndromes (<jats:styled-content style="fixed-case">MDS</jats:styled-content>), continued evidence from large prospective clinical trials evaluating the efficacy and safety of iron chelation therapy in this patient population is warranted.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>The safety and efficacy of deferasirox was examined in a prospective, open‐label, single‐arm, multicenter trial of transfusion‐dependent patients with International Prognostic Scoring System low‐ or intermediate‐1‐risk <jats:styled-content style="fixed-case">MDS</jats:styled-content> and evidence of transfusion‐related iron overload. The effects of deferasirox therapy on hematological response and disease progression were also examined.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Of 159 participants enrolled from 37 Italian centers, 152 received ≥1 dose of deferasirox (initiated at 10–20 mg/kg/day and titrated as appropriate), and 68 completed the study. Of 84 patients who discontinued deferasirox therapy, 22 died during the trial, and 28 withdrew due to an adverse event (<jats:styled-content style="fixed-case">AE</jats:styled-content>). Fourteen treatment‐related grade 3 <jats:styled-content style="fixed-case">AE</jats:styled-content>s occurred in 11 patients, whereas no grade 4 or 5 drug‐related <jats:styled-content style="fixed-case">AE</jats:styled-content>s were reported. Significant risks for dropout were a higher serum ferritin level at baseline, a higher <jats:styled-content style="fixed-case">MDS</jats:styled-content>‐Specific Comorbidity Index, and a shorter diagnosis–enrollment interval. Median serum ferritin level fell from 1966 ng/mL to 1475 ng/mL (<jats:italic>P</jats:italic> < 0.0001). The cumulative incidence of transfusion independence, adjusted for death and disease progression, was 2.6%, 12.3%, and 15.5% after 6, 9, and 12 months, respectively.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Deferasirox therapy in transfusion‐dependent patients with <jats:styled-content style="fixed-case">MDS</jats:styled-content> was moderately well tolerated and effectively lowered serum ferritin levels. Positive hematological responses were observed, and a subset of patients achieved transfusion independence.</jats:p></jats:sec>