Background: Thalassemia is an inherited hematological disorder categorized by a decrease or absence of one or more of the globin chains synthesis. Aim: To investigate the diagnostic value of serum Osteoprotegerin in B-Thalassemia patients, and assay as an early biomarker for osteoporosis. Patients and methods: This case–control and comparative study was conducted on 80 subjects at hematology clinic Beni-Suef university hospital. It was held from It was held from June 2021 to June 2022. Results: There was a statistical significant high mean of Osteoprotegrin level with p-value <0.05 among thalassemia cases versus controls. Also significant lower mean in control group in comparison to both thalassemia subtypes (p-value <0.001), with no difference between the two thalassemia types (intermedia and major) (p-value 0.05). but it is higher in thalassemia major than thalassemia intermedia . Thalassemia cases show a positive correlation between age and hemoglobin levels, with a significant negative correlation between PLT and spine and femur scores. Ferritin levels are also negatively correlated with spine and femur scores p<0.05. Conclusion: Osteoporosis is a major issue in β thalassemia patients, with osteoprotegrin (OPG) playing a crucial role in bone formation. Elevated OPG may compensate for osteoporosis in beta thalassemia patients, while reduced OPG may decrease osteoblast action. DEXA scans are the gold standard for early detection.