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This study was designed to assess the efficacy of N-acetylcysteine (NAC) on the reduction of oxidative stress in chronic hemodialysis (HD) patients through measurement of total serum anti-oxidant capacity. In this randomized, double-blind, controlled clinical trial, the efficacy and safety of NAC in reduction of oxidative stress was evaluated in 40 chronic HD patients. The study was conducted at the HD Department of the Golestan Hospital, Ahvaz, Iran. Data were analyzed using SPSS version 19. Paired samples test showed that the mean score of the serum level of total anti-oxidant capacity (TAC) increased from 26.39 ± 17.03 to 33.26 ± 18.8 (Pvalue = 0.01) and from 24.02 ± 16.47 to 25.38 ± 17.04 (P = 0.1) in the NAC and placebo groups, respectively. Difference in the mean TAC changes between groups was statistically significant (P= 0.042). In our study, NAC administration could reduce oxidative stress in chronic HD patients. No major side-effects were observed.