Introduction: Tacrolimus is a macrolide calcineurin inhibitor which has been shown to decrease acute and chronic rejection, improved renal function over the longterm post-transplant. Tacrolimus is considered the drug of choice in immunosuppressive therapy for chronic diseases irresponsive to corticosteroids, autoimmune diseases and organ transplantation system. Aim: The aim of the investigation was to study the effect of the immunosuppressive drug Tacrolimus on the lingual mucous membrane and salivary glands of treated rats through hematoxylin and eosin stained sections to detect any microscopic changes in the structure of the mucous membrane and salivary glands of the tongues & Masson's trichrome stained sections for detection of the integrity of collagen. Material and Methods: Thirty healthy adult male albino rats with body weight ranging from 150 to 180 gm were used in this investigation. The animals were divided into two groups 15 animals each. Group 1: served as control, group 2: animals were treated with the immunosuppressive drug tacrolimus dissolved in distilled water in a daily oral dose of 0.5 mg/kg body weight. At the end of the experiment the rats of different groups were euthanized by cervical dislocation. The tongues were dissected out, fixed, processed, embedded in paraffin, sectioned and stained with hematoxylin and eosin for histological evaluation & Masson's trichrome stain for demonstration of collagen fibers. Results: The light microscopic examination of group I showed the normal histological features of both surface epithelium and underlying lamina propria, while group II Treated with tacrolimus revealed atrophic and degenerative changes that involved the surface epithelium and lamina propria of both the dorsal and ventral surfaces of the tongue as well as the lingual salivary glands. Conclusion: Tacrolimus administration showed structural alterations in the lingual mucous membrane and the lingual salivary glands which will certainly affect the taste sensation.