Background β-Thalassemia major is characterised by ineffective erythropoiesis and lifelong transfusion dependence, leading to progressive iron overload. Although serum ferritin is widely used to assess iron burden, it does not reliably reflect erythropoietic activity or transfusion requirement. Hepcidin, a key regulator of iron homeostasis, is known to be dysregulated in thalassemia; however, its relationship with transfusion burden remains incompletely defined, particularly in African populations. Objective To evaluate serum hepcidin levels in patients with β-thalassemia major and to examine their association with transfusion requirement, serum ferritin, and selected erythropoietic markers. Methods This cross-sectional study was conducted at tertiary hematology centres in South Africa between January 2023 and December 2024. Patients with confirmed β-thalassemia major receiving regular transfusion therapy were enrolled. Clinical data, transfusion history over the preceding 12 months, and laboratory parameters were collected. Serum hepcidin was measured using enzyme-linked immunosorbent assay, while ferritin and hematologic indices were assessed using standard laboratory methods. Correlation analyses and multivariable regression were performed to identify predictors of transfusion requirement. Results Seventy-two patients were included in the analysis. Median serum hepcidin levels were low relative to iron burden, while serum ferritin levels were markedly elevated across the cohort. Serum hepcidin demonstrated a significant inverse correlation with annual transfusion volume and transfusion frequency. In contrast, no consistent correlation was observed between serum hepcidin and ferritin levels. Hepcidin also showed a strong inverse association with reticulocyte count and a positive association with pre-transfusion haemoglobin. In multivariable analysis, serum hepcidin remained an independent predictor of transfusion requirement, whereas ferritin did not. Conclusions In patients with β-thalassemia major, serum hepcidin levels reflect erythropoietic activity and transfusion burden rather than iron stores. The dissociation between ferritin and hepcidin highlights the limitations of ferritin as a functional biomarker in this setting. Hepcidin may serve as a useful adjunct marker for assessing disease severity and transfusion dependency, with potential implications for risk stratification and future therapeutic strategies.

β-thalassemia major; Hepcidin; Transfusion requirement; Ferritin; Ineffective erythropoiesis; iron metabolism