Patients with higher-risk myelodysplastic syndromes (HR-MDS), if left untreated, have lower overall survival (OS), progress to acute myeloid leukemia (AML), and increased burden. This systematic literature review (SLR) identified comprehensive evidence of clinical burden of disease among patients with lower to HR-MDS. Literature search of English publications from 2011-2021 was conducted in Embase®, MEDLINE® and MEDLINE®-In-process to identify relevant studies fulfilling pre-defined inclusion criteria. Data on study characteristics, patient demographics and clinical burden were extracted. A total of 67 studies fulfilled the eligibility criteria. Patients with HR-MDS had lower OS and were four-times less likely to survive compared with lower-risk MDS (LR-MDS) over 85 months (HR, 4.46; CI, 2.8-7.1; p<0.001). Presence of comorbidities, karyotyping and transfusion dependency were predictive of low survival with HR-MDS. Progression to AML was time-dependent and significantly associated with decreased survival (HR, 1.80; CI, 1.27-2.55; p<0.001). Patients with HR-MDS had a high propensity and took less time for AML transformation than patients with LR-MDS. The AML transformation rate increased by 1.5-fold among HR-MDS patients, from first to second year of MDS diagnosis. Cardiovascular disorders and diabetes were common comorbidities, while anemia, thrombocytopenia and neutropenia constituted a major symptom burden. The impact of IPSS-R categories on EuroQoL-5D scoring, was only marginal, and varied per age, gender, comorbidities and transfusion requirement (p<0.001). Among patients with HR-MDS, blood transfusion led to reduction in symptoms of anemia and fatigue (p=0.016). Low quality of life (QoL) was associated with reduced survival. Age, gender, comorbidities and blood transfusion (p<0.001) significantly impacted QoL. There is a substantial clinical burden with MDS; age, gender, cytogenetics, comorbidities and blood transfusion being the predominant factors that predict survival and QoL among these patients. A significant proportion of patients with MDS transform to AML. Thus, there is a clearly identified need for more frontline therapies focusing on improving symptoms and OS, particularly among patients with HR-MDS.