Background: Oxidative stress due to iron accumulation in patients with beta-thalassemia major (BTM) causes complications such as tissue damage and destruction. This study aimed to assess the association between the serum prooxidant/antioxidant balance (PAB) and blood parameters in patients with BTM. Methods: This cross-sectional study included 92 patients with BTM. In this study, PAB was measured using an enzyme-linked immunosorbent assay (ELISA). Serum ferritin, blood urea nitrogen (BUN), creatinine (Cr), alanine aminotransferase (ALT), aspartate aminotransferase (AST), thyroid-stimulating hormone (TSH), total cholesterol (TC), triglyceride (TG), complete blood cell count (CBC), and history of blood transfusion were recorded. The association of the blood parameters was assessed across the tertiles (T) of serum PAB (highest T vs. lowest T). Results: The results showed that high serum ferritin was directly associated with serum PAB [odds ratio (OR), 12.80; 95% confidence interval (CI), 2.98‒54.91; T3 vs. T1]. Also, direct associations were found for high TC (OR, 4.97; 95% CI, 1.42‒17.32; T3 vs. T1), high ALT (OR, 4.95; 95% CI, 1.33‒18.46; T3 vs. T1) and high TSH (OR, 3.78; 95% CI, 1.10‒13.02; T3 vs. T1). Conclusion The findings of the present study showed that serum PAB levels were directly associated with ferritin, ALT, TC, and TSH levels. This indicates that improvements in blood parameters, especially ferritin and TSH levels, occur by ameliorating oxidative stress in patients with BTM.