Background: Increased liver stiffness can be result of increased liver iron concentration (LIC) which may not yet be reflected in the liver fibrotic status. The objective of our study was to examine relationship between hemochromatosis, liver stiffness, and serum ferritin level in transfusion-dependent patients. Methods: All transfusion-dependent patients aged between seven and 60 years referred for evaluating LIC status by magnetic resonance imaging (MRI) followed by two-dimensional ultrasonography shear wave elastography (2D-SWE) were included in this study. Results: The optimal cut point for prediction of severe hemochromatosis using median SWE (kPa) and SWV (m/s) was ≥ 7.0 kPa and ≥ 1.54 m/s, respectively, with sensitivity of 0.76 (95% confidence interval [CI] 0.55, 0.91) and, specificity of 0.69 (95%CI 0.53, 0.82). When combing the optimal cut point of SWE (kPa) at ≥ 7.0 and serum ferritin ≥ 4123 ng/mL, the sensitivity increased to 0.84 (95%CI 0.64, 0.95) with specificity of 0.67 (95%CI 0.50, 0.80), positive predictive value (PPV) of 0.60 (95%CI 0.42, 0.76), and negative predictive value (NPV) of 0.88 (95%CI 0.71, 0.96). Simultaneous tests of 2D-SWE and serum ferritin for prediction of severe hemochromatosis showed the highest sensitivity of 84% (95%CI 0.64-0.95), as compared to 2D-SWE alone at 76% (95%CI 0.55, 0.91) or serum ferritin alone at 44% (95%CI 0.24-0.65). Conclusions: We recommend measuring both 2D-SWE and serum ferritin in short interval follow up patients. Adding 2D-SWE to the management guideline will help in deciding if aggressive adjustments of iron chelating medication in indicated in patients suspicious for severe hemochromatosis.