Sucralose and saccharin-cyclamate mixture are considered as safe commercial artificial sweeteners with many health authorities instead of natural sugar. We aimed to reveal their effects on the physiological, immunological and histological profiles. Mice were given sucralose (0.3 mg/ml) or saccharin-cyclamate mixture (20 mg/ml) in drinking water for 8 and 16 weeks. Only sucralose caused a temporary significant increase in blood glucose after 8 weeks that was eliminated after 16 weeks. WBCs count was decreased significantly after 16 weeks of sucralose administration. Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), blood urea nitrogen (BUN) and creatinine (Cr) recorded an increase at 8 and 16 weeks due to the two artificial sweeteners intake. Both artificial sweeteners induced a significant increase in interleukin (IL-) 6, tumor necrosis factor-alpha (TNF-α) and circulating lipopolysaccharides (LPS) levels with a progress from 8th to 16th weeks post administration. Both sugars, especially sucralose, caused a severe damage in kidney, liver, pancreas and urinary bladder. Data indicated the adverse effect of Sucralose and saccharin-cyclamate mixture, their consumption can cause a severe inflammation in liver, kidney, pancreas and urinary bladder. Moreover, they may interrupt the intestinal barriers leading to an increase in circulating LPS and pro-inflammatory cytokine secretions.