Analyses suggest iron overload in red blood cell (
RBC) transfusion‐dependent ( TD) patients with myleodysplastic syndrome ( MDS) portends inferior overall survival ( OS) that is attenuated by iron chelation therapy ( ICT) but may be biassed by unbalanced patient‐related factors. The Canadian MDSRegistry prospectively measures frailty, comorbidity and disability. We analysed OSby receipt of ICT, adjusting for these patient‐related factors. TDInternational Prognostic Scoring System ( IPSS) low and intermediate‐1 risk MDS, at RBC TD, were included. Predictive factors for OSwere determined. A matched pair analysis considering age, revised IPSS, TDseverity, time from MDSdiagnosis to TD, and receipt of disease‐modifying agents was conducted. Of 239 patients, 83 received ICT; frailty, comorbidity and disability did not differ from non‐ ICTpatients. Median OSfrom TDwas superior in ICTpatients (5·2 vs. 2·1 years; P< 0·0001). By multivariate analysis, not receiving ICTindependently predicted inferior OS, (hazard ratio for death 2·0, P= 0·03). In matched pair analysis, OSremained superior for ICTpatients ( P= 0·02). In this prospective, non‐randomized analysis, receiving ICTwas associated with superior OSin lower IPSSrisk MDS, adjusting for age, frailty, comorbidity, disability, revised IPSS, TDseverity, time to TDand receiving disease‐modifying agents. This provides additional evidence that ICTmay confer clinical benefit.