Background: Hemodialysis patients (HD) always suffer from fatigue, which is associated with poor health-related quality of life (HRQoL) in this population. Purpose: To evaluate the intensities of fatigue in HD patients, we evaluated the impact of selenium and thiotacid on their fatigue level and the reflection of their antioxidant effect on HRQoL. Methods: This study was a prospective, randomized controlled clinical trial. It was carried out in two dialysis units of Ain Shams University Hospitals. The study protocol was approved by the Research Ethics Committee (REC), Faculty of Medicine, Ain Shams University, No. (FMASU MD, 381/2018). Informed consent was obtained from all individual participants included in the study. Between August 2018 and January 2019, HD patients who completed the Arabic Translated form of the Fatigue Severity Scale (FSS). FSS was assessed at baseline and three months after starting therapy with selenium or thiotacid. Results: All HD patients were suffering from severe fatigue states (mean fatigue scores of 6.04, 6.09, and 6.115) for the control, selenium, and thiotacid groups, respectively. After three months, the mean fatigue score elevated from 6.04 to 6.518 in the control group. Supplementation with selenium and thiotacid positively affected the reduction of fatigue score by 46.5% and 44.19% in selenium and thiotacid groups, respectively. There was no significant difference between the two drugs in the improvement of fatigue state in both treated groups. Conclusion: Selenium or thiotacid supplementations successfully decreased fatigue in HD patients