Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis resulting in refractory cytopenias. Red blood cell (RBC) transfusions can improve anemia; however, prolonged transfusion dependence (TD) is associated with increased morbidity and mortality. Disease-modifying therapy (DMT) for MDS can reduce transfusion requirements, although the optimum timing of DMT initiation is unclear. This retrospective study analyzed linked SEER registry and Medicare claims (2006-2012) to estimate the impact of DMT-initiation (azacitidine, decitabine, or lenalidomide) timing (≤ 3 vs.>3months from start of TD) on the likelihood of achieving transfusion independence (TI) among 508 TD patients with MDS. Mean time to DMT was 28days for early initiators (n=351) and 187days for late initiators (n=157). Fewer early initiators used erythropoiesis-stimulating agents before achieving TI versus late initiators (61.5% vs. 73.9%; P=0.007). In multivariate analyses, early DMT initiation predicted TI achievement (HR, 1.69; P<0.001); patients who met minimum active therapy-exposure requirements were more likely to achieve TI (HR, 2.12; P<0.001). Higher rates of TI were associated with reduced time between onset of TD and DMT initiation. Similarly, patients meeting the minimum treatment-exposure threshold had higher TI rates.