Background :Caffeine is one of the most widely consumed substances in the world. The main sources of caffeine in society are coffee or tea The cytotoxicity of caffeine may be due to its ability to trigger apoptosis   Material and methods :A total number of 30 adult male albino rats (150-200 g) were used and were divided randomly into five equal  groups (n=6 ) control group: 6  rats were  I.P injected with sterile: Group II & IIa :12 rats were I. P. injected with single daily dose (2.5 mg/100g body weight/day) for three months this dose is equivalent to minimum human dose. Group IIa: 6 rats stopped treatment and left for one month after the period of treatment.Group III & IIIa: 12 rats were I.P. Injected with single daily dose (10 mg/100g body weight/day) for three months this dose is equivalent to maximum human dose. Group IIIa: 6 rats stopped treatment and left for one month after the period of treatment Samples from the submandibular  salivary glands were fixed in 10% buffered neutral formalin and prepared routinely for paraffin sectioning and staining for histopathological changes and immuno- histochemical investigations of apoptotic cell antigen (Annexin A5).   Results : Histopathological examination of caffeine treated rats revealed marked  changes in glandular architecture, the acini became shrunkn with loss of their rnormal circular arrangement and their cytoplasm was vacuolated. Some serous cells degenerated and replaced by eosinophlic material. The nuclear changes appeared in form of (pleomorphism, hypertrophy, hyperchromatism and pyknosis), numerous normal and abnormal mitotic Figures were detected. Intercalated and excretory ducts were dilated. , blood vessels were dilated and congested. The immuno expression of Annexin A5 in the cytoplasmic basement membrane of the ductal cells was intense and highly significant. Changes were more aggressive in (group III). Recovery of some histological changes were observed especially in group received lower dose of  caffeine .   Conclusion: Excessive use of Caffeine markedly affect the histological structure of submandibular salivary gland. These changes could be reversible after caffeine stoppage if the doses is small while the histopathological changes of the gland is irreversible if the doses is large .