Background: ESAs are used in first-line treatment for symptomatic or transfusion-dependent anemia in patients (pts) with LR-MDS. Ultimately, the majority of pts with LR-MDS who receive an ESA will experience ESA treatment failure. This real-world (RW) study aims to describe pt characteristics, treatment patterns including ESA use, and outcomes in pts with LR-MDS. Methods: A retrospective, observational, US multisite, cohort chart review of adult pts diagnosed with LR-MDS between January 1, 2015 and June 24, 2020 was conducted. Eligible pts had not received luspatercept or participated in a clinical trial and had ≥ 1 year of follow-up after LR-MDS diagnosis, unless follow-up was < 1 year due to death during this interval. Demographics, clinical characteristics, treatment patterns, and outcomes were summarized using descriptive statistics. Median duration of therapy (DOT) was estimated using the Kaplan-Meier method. Results: Among 338 eligible pts, median age at LR-MDS diagnosis was 70 years (range: 19–100), 55% were female, 71% were White, 17% had known detection of del(5q), and ring sideroblast status was known to be positive for 7%. Transfusion independence within the 8 weeks prior to diagnosis (TI8) was reported for 48% of eligible pts and 17% had intermediate-1/ intermediate disease risk by IPSS/ IPSS-R risk classification. Within the study follow-up time (median of 28.3 months from diagnosis), 76% of pts had received systemic therapy for MDS (median DOT: 29.2 months). An ESA was used in 56% (n = 190) of pts, of whom 38% received red blood cell (RBC) transfusions during ESA treatment. Of those receiving systemic treatment for LR-MDS, 11% were hospitalized for reasons that physicians reported were related to MDS treatment complications. At the time of data collection, 30% of pts had died. Among 38 pts determined to have failed ESA treatment by abstracting physicians, 11% had TI8, 34% had intermediate-1/ intermediate disease risk, 82% received RBC transfusions during ESA treatment, 26% required hospitalization that abstracting physicians reported was related to MDS treatment complications, 32% continued to receive ESA post-failure, and 53% were deceased at data collection. Conclusions: Results from this RW study indicate that a higher proportion of pts with LR-MDS who experienced ESA treatment failure according to abstracting physicians had intermediate-1/ intermediate disease risk at diagnosis, were transfusion dependent at diagnosis, required RBC transfusions during ESA treatment, were hospitalized for reasons related to MDS treatment complications, and had poor short-term survival. Nearly a third of pts who experienced ESA treatment failure still received an ESA after initial failure. In summary, findings from this study indicate that pts with LR-MDS who experience ESA treatment failure are likely to have worse outcomes.