Background: Myelodysplastic Syndrome (MDS) is a complex group of neoplasms that arises from abnormalities in the bone marrow's hematopoietic stem cells, leading to ineffective blood cell production. Frailty signifies increased vulnerability to internal and external stressors, with its impact on survival in MDS gaining recognition. We conducted a retrospective analysis to explore the impact of frailty on hospitalized MDS patients and its association with unfavorable hospital outcomes. Methods: National Inpatient Sample (NIS) 2019 and 2020 was utilized to identify the patients admitted with a primary diagnosis of MDS and had a concurrent diagnosis of Frailty. The Primary outcome was Mortality, and secondary outcomes included length of stay, total cost of hospitalization, and other adverse in-hospital outcomes. Multivariate logistic regression analysis was used to calculate the outcomes after adjusting for baseline sociodemographic characteristics. Results: A total of 17,000 patients were admitted with a primary diagnosis of MDS, among whom 4,285 (25.20%) patients had a concurrent diagnosis of Frailty. The mean age of patients with and without Frailty was 75.75 (+/-14.01) and 71.54 (+/-14.68), respectively, p<0.001. After adjusting for confounding variables, Frailty was considered an independent predictor of mortality in MDS patients (OR=1.80 (1.22-2.64); p=0.003). Patients with Frailty had a prolonged length of stay in the hospital (8.62 days(3.2-9.6) without and 11.56 days (4.6-12.1) with Frailty, P<0.001), as well as an increased total cost of hospitalization ($ 132159 (3256-23651) without and $173898 (5317-389146) with Frailty, p<0.001). Additionally, Frailty was associated with an increased likelihood of sepsis (OR=2.02 (1.33-3.06); p=0.001), acute kidney injury (OR=1.22 (1.02-1.50); p=0.04), major depressive disorder (OR=1.51 (1.19-1.91); p=0.001), and a higher association with chemotherapy (OR=3.46 (1.21-9.91); p=0.021) and palliative care (OR=2.23 (1.72-2.90); p<0.001). However, frail patients were less likely to receive blood transfusions (OR=0.73 (0.61-0.88); p=0.001), and no difference was noted in the risk of platelet transfusions (OR=0.95 (0.73-1.25); p=0.763). Conclusions: Frailty is considered an independent predictor of mortality and is associated with increased healthcare resource utilization along with other adverse in-hospital outcomes. Careful and thorough identification of frailty and its effective management is crucial for improving outcomes, reducing mortality, and enhancing the quality of life for patients with debilitating MDS.