OBJECTIVES: To describe healthcare resource utilization (HRU) and costs in patients with myelodysplastic syndromes (MDS) treated with hypomethylating agents (HMA) with a focus on HMA-treatment success and failure. METHODS: SEER-Medicare data (01/2006-12/2016) were used to identify adults diagnosed with MDS (SEER: 01/2009-12/2015) initiated on HMA (index date). HMA-treatment success (indicators, including: ≥7 HMA cycles, stem cell transplant, and transfusion independence) or failure (indicators, including: acute myeloid leukemia [AML], AML-like chemotherapy, and death) was assessed using a claim-based algorithm. HRU and costs (payer’s perspective, 2018 USD) were assessed from the index date up to 1-year post-index for the overall sample and stratified by HMA-treatment success or failure status. Among patients with HMA-treatment failure, HRU and costs were also assessed from 1-month pre-failure up to 1-year post-failure. RESULTS: 3,046 patients were included (mean age: 77.4 years; females: 36.8%; azacitidine: 77.4%, decitabine: 22.6%). Rates of HMA-treatment success and failure were 44.4% and 76.2%, respectively (20.6% of patients had HMA-treatment success followed by failure). Overall, patients had 15.2 inpatient admissions per-100-patient-per-month (median follow-up: 5.9 months). Patients with HMA-treatment success only had 7.5 inpatient admissions per-100-patient-per-month (median follow-up: 12.0 months), and those with HMA-treatment failure had 20.4 and 35.3 inpatient admissions per-100-patient-per-month pre- and post-HMA-treatment failure, respectively (median follow-up 4.3 and 1.8 months, pre- and post-HMA-treatment failure, respectively). Mean total healthcare costs were $12,494 per-patient-per-month in the overall sample, $8,069 per-patient-per-month among patients with HMA-treatment success only, and $13,809 and $19,242 per-patient-per-month pre- and post-HMA-treatment failure, respectively. Outpatient costs (68.3%) were the main contributor of total healthcare costs for the overall sample, while inpatient costs (80.3%) were the main driver post-HMA-treatment failure. CONCLUSIONS: Approximately three quarters of patients with MDS failed HMA therapy within 6 months of HMA treatment initiation; these patients had more inpatient admissions, which translated into higher healthcare costs after HMA-treatment failure.