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Sodium sesquicarbonate also known as Sodium sesquicarbonate dihydrate (SSD) has been used globally for centuries in food and traditional medical practices. There is paucity of scientific information on the safety of this common food additive. This study was designed to find out if the oral administration of SSD is capable of generating oxidative stress in erythrocytes, liver and kidney using albino rats as experimental models. The total number of animals used for this study was fifteen. The experimental animals were grouped into three. There were five animals in each group. The rats in the first group which was the control group, were dosed with 1 ml distilled water, while groups 2 and 3 were treated with 400 mg/kg and 800 mg/kg body weight (bw) of SSD, respectively, once daily per os for 28 days. After the duration of treatment, the erythrocytes, hepatic and kidney tissues were processed for the analysis. The biomarkers of oxidative stress, superoxide dismutase (SOD), catalase; and thiobarbituric acid reactive substances/ malondialdehyde (TBARS/MDA) were assayed. The result indicated that catalase enzyme activity was overexpressed in the red blood cells, liver and kidneys of the group that consumed the lower dose of SSD. The dose-dependent increase in the lipid peroxidation of the tissues as indicated by increased levels of MDA in the erythrocytes and TBARS in the tissues of the treated groups was significant (P < 0.05). The SOD enzyme activity in all the tissues assayed showed a dose-dependent decrease, which was significant at the probability level of 0.05. The consumption of SSD therefore caused lipid peroxidation and reduction in activity of the antioxidants present in the tissues studied.