Aim Of The Study:Artificial sweeteners such as aspartame (APM) are widely consumed nowadays, yet their long-term health impact is uncertain. The present work aimed to investigate the effect of short and long term administration of two different doses of APM (40mg/kg.b.w &80mg/kg.b.w) on the structural features of von Ebner’s salivary glands, circumvallate tongue papillae and taste buds.Materials And Methods:Sixty six male adult albino laboratory rats with an age ranges from 3 to 4 months and weight range from 200 to 250 g were utilized in the present study. Pure Aspartame powder was purchased from Chemical Industries Development (CID) pharmaceutical Company, Cairo, Egypt. The animals were divided into 3 groups; Group I: consisted of 22 rats They were daily administrated distilled water by means of gastric tube and considered control group. Group II: consisted of twenty two rats. They were given APM (40 mg/kg.b.w) dissolved in distilled orally, daily and by means of gastric tube for 3&6 months. Group III: consisted of 22 rats. They were given APM (80 mg/kg.b.w) dissolved in distilled orally, daily and by means of gastric tube for 3&6 months. Eleven rats from each group were sacrificed at the end of the third and sixth months under chloral hydrate anesthesia. The tongue was subsequently dissected and prepared for Histological examination using H&E stain, histochemical examination using PAS/AB reaction and immunohistochemical staining using PCNA antibody.Results:The histopathological results after short term administration of APM in both groups showed less degenerative changes compared with long term administration, it was seen in form of changes in the shape of the circumvallate papilla to be inverted with wide base and narrow surface and the trough was abnormally widened. Taste buds revealed distorted barrel shaped cell arrangement. However, some areas along the trough were devoid of taste buds. The von Ebner’s salivary glands showed severe atrophy and reduction of serous acini. Acinar and ductal cells showed indistinct boundaries. Mucous transformation into demilunes of von Ebner’s was seen between the serous secretory portions. Long administration of APM showed more aggravated signs of degeneration with loss of acinar and ductal architecture and appearance of signs of premalignancy. Histochemical examination showed moderate decrease in PAS positive reaction of vonEbner’s salivary glands in the short term administration of APM, which was extremely diminished in distribution after long term administration. Immunohistochemical reaction showed the highest rate of proliferative activity of the cells was recorded after long term administration of APM.Conclusion:Aspartame is considered as a very harmful premalignant drug on both short and long term administration, and the severity of changes associated with aspartame administration to albino rats was both dose and time dependant. So, the public should be altered about the adverse effects of aspartame.