Background: Submandibular salivary glands are responsible for secretion of major amount of saliva which is important for normal oral environment of the oral cavity. Aim: to evaluate the effect of the Immunosuppressive drug Sirolimus on structure and immunohistochemistry of the submandibular salivary glands of the rats. Material and Methods Forty healthy adult male albino rats (body weight 150 -180 gram) were divided into two equal groups 20 animals each. Group 1 served as controls while group 2 were treated with the immunosuppressive drug sirolimus (rapamycin). Control group were subdivided into two subgroups subgroup 1.1: received ethanol and saline in comparable volume to group 2 and same route of administration while subgroup 1.2 were left untreated. After 3 months, rats were sacrificed and specimens of the right side of submandibular salivary glands were stained with H & E and Immunoperoxidase. While specimens of the left side were examined with transmission electron microscope. Results: Histologically, by H & E, both control subgroups showed normal structure of submandibular salivary gland. While, rats administrated sirolimus showed altered structure. Using TEM, the ultrastructural of submandibular salivary glands of both control subgroups showed normal architecture. While, sirolimus treated- group revealed degeneration in the glands acinar and ductal cells. Immunohistochemical findings showed normal staining reactivity of submandibular salivary gland of the control group while, sirolimus-treated group showed marked reduction in their staining reaction. Conclusion:Sirolimus administration cause structural and ultrastructural alterations in the parenchymal and stromal elements of the submandibular salivary gland that affect the salivary secretion and may lead to detrimental effect on oral health.