Abstract: The present study aims to evaluate the effect of antioxidation and hypomethylation on the genotoxicity and apoptosis induced in mice by arsenic trioxide (As2O3) in normal adult male SWR/J mouse. Animals were treated with intraperitoneally (ip) injected with (2.65, 5.35 or 10.70 mg kg-1 b.wt. of As2O3 which represent 0.25, 0.50 or 1 of LD50, respectively) and killed 24 h later. Another groups were treated with 30 mg kg-1 b.wt. of antioxidant and hypermethylizing agent butylated hydroxy toluene (BHT) 1 h prior to As2O3 administration. Another different groups were treated with three doses of 5-azacitidine (5-AzaC) 5 mg kg -1 b.wt. As2O3 administered after 6 days of the last dose. The three single doses of As2O3 significantly (p<0.05) increased the rate of total structural chromosomal aberrations (CAs) compared with the negative control. No significant effect was observed in the combined treatment with BHT or 5-AzaC compared with single treatments. The histopathological analyses of mice liver cells showed significantly (p<0.05) increased in apoptosis markers in all three single doses of As2O3 compared with the negative control and also significantly (p<0.05) increased with combined treatment with BHT at low and high doses compared with single doses. This study showed that administration of As2O3 had a negative effects as represented in CAs test, antioxidant as represented in apoptosis markers and 5-AzaC as represented in rate of pulverized chromosomes, centromeric attenuations, number of polyploidy cells.