Myelodysplastic syndromes (MDS) are associated with anemia and the need for blood transfusions. In clinical trials, luspatercept reduced transfusion dependency among patients with lower-risk MDS. This United States (US) study describes real-world clinical outcomes pre- and post-luspatercept initiation among patients with MDS. Symphony Health Integrated Dataverse claims data (August 1, 2010-December 29, 2022) were used to identify patients with MDS treated with luspatercept (first luspatercept claim = index date). Transfusion-dependent (TD) or non-TD (NTD) patients at baseline were described as 8-week transfusion-independent (TI) or as maintaining NTD, respectively, if they had no transfusion for 8 weeks in the 6 months post-index (similarly for 12, 16, and 24 weeks). Transfusion status was measured overall and among patients who were baseline NTD, TD, TD and exposed to erythropoiesis-stimulating agents (ESA) (TD+ESA-exposed), MDS with ring sideroblasts (RS) (MDS-RS), and MDS-non-RS. MDS-related treatments were measured pre- and post-index. Among the 871 patients who received luspatercept (mean age: 74.7 years), 87.4 % achieved 8-week TI/maintained NTD within 6 months post-index, 64.9 % of patients did not receive additional MDS-related treatments post-luspatercept initiation (median follow-up: 14.8 months), 98.5 % of baseline NTD patients maintained 8-week NTD 6 months post-luspatercept initiation, and 88.6 % did not receive a transfusion for 24 weeks. Baseline TD (64.2 %) and TD+ESA-exposed (64.2 %) patients achieved 8-week TI 6 months post-luspatercept initiation. Eight-week TI proportions were similar between MDS-RS (89.8 %) and MDS-non-RS (84.8 %) subgroups. These findings corroborate clinical trial data by showing the high effectiveness of luspatercept among real-world patients with MDS in the US.