Introduction: β-thalassemia is a genetic blood disease characterized by ineffective erythropoiesis due to defective hemoglobin production that manifests as potentially fatal anemia. Patients with β-thalassemia rely on regular, lifelong red blood cell transfusions (RBCTs) for survival and suffer from multi-system complications, physical manifestations, and decreased health-related quality of life (HRQoL) due to iron overload and continual RBCTs. This literature review aims to describe the disease burden associated with β-thalassemia. Methods: Electronic databases (MEDLINE®, Embase®, Cochrane Library) were searched to identify articles in the English language assessing the clinical, economic, and humanistic burden of β-thalassemia in North America and Europe. Articles were selected based on predefined criteria including appropriate study design, disease state, country, and outcome measures. Results: Patients with β-thalassemia who received regular RBCTs were significantly more likely to develop ≥ 1 iron overload-related comorbidity than matched, non-thalassemia controls (P < 0.0001). Other iron-related issues included cardiac disease (observed in 13-30% of patients), hypogonadism (17-22%), diabetes (10-18%), osteoporosis (16%), hypothyroidism (12%), liver disease (4%), and hypoparathyroidism (2%). RBCTs also introduced the risk of transfusion reactions (48-50%), infections (24-65%), and development of alloantibodies (19-23%). Mortality rate for the US population was 1.9%. The direct annual cost per regularly transfused patient with β-thalassemia was significantly higher than in matched controls (USD 128,062 vs USD 5,438; P < 0.001; 2016 USD). The main annual cost drivers per patient were iron chelation therapy (48%; USD 61,974) and RBCTs (31%; USD 39,723). Indirect costs for β-thalassemia were impacted by unemployment, reported at 33% among patients with β-thalassemia versus 24% for the general US population. Patients scored significantly worse on 5 subdomains (physical functioning, role-physical, general health, social functioning, and role-emotional) of the Short Form-36 (SF-36) HRQoL questionnaire compared with the general US population (all P < 0.0001) with the greatest impairments seen in the general health subdomain (P < 0.0001). Clinically meaningful reductions in physical functioning, role-physical, and general health scores were observed for patients with β-thalassemia aged < 65 years with transfusion-related iron overload. Bodily pain was reported by 56-69% of patients with β-thalassemia, and pain interfered with patient physical and emotional functioning HRQoL outcomes. Increasing age correlated with higher numbers of pain responses (P < 0.001). Psychiatric comorbidities were found in 24% of patients with β-thalassemia, and mood disorders, including depression and anxiety, were associated with overall significantly poorer physical and mental HRQoL (P < 0.001). Conclusions: β-thalassemia is associated with a substantial clinical, economic, and humanistic burden in the USA. Patients with β-thalassemia experience reduced life expectancy, significant comorbidities, considerable direct healthcare costs, unemployment, and impaired HRQoL. There is a need for more effective management and therapeutic options for these patients. Disclosures Mearns: Celgene Corporation: Employment. Udeze:Celgene Corporation: Employment. Copher:Celgene Corporation: Employment. Sheth:CRSPR/Vertex: Other: Clinical Trial Steering committee; Apopharma: Other: Clinical trial DSMB; Celgene: Consultancy.