Background: The aim of this study is to develop new perspectives to prevent or reduce potential organ damage due to iron-mediated oxidation in thalassemia major patients. Methods: Seventy patients were included in this study. Blood samples were taken from the patients before and after transfusion. Total thiol, native thiol, disulfide, disulfide/native thiol percentage ratio, ischemia modified albumin (IMA), total antioxidant status (TAS), total oxidant status (TOS), and ferroxidase levels were determined. Additionally, undepleted thiol level (UTL) was determined as a new parameter associated with organ damage. Results: After transfusion, the levels of native thiol, total thiol, disulfide, TAS, ferroxidase, and TOS were higher, while the IMA levels and disulfide/native thiol percent ratio were lower. Significant correlations were found between antioxidant and oxidant tests before and after transfusion. Additionally, a negative correlation was found between the TOS and UTL levels of the patients measured before the transfusion. Conclusion: In the present study, transfusion therapy increased both oxidation and the antioxidant levels. In addition, the term UTL has been introduced as a parameter that enables the determination of the oxidation level that may cause potential organ damage in transfusion-dependent thalassemia patients.