Aims:The objective of this study is to evaluate the effects of oral methotrexate on the oral tissues of rabbits. Materials and Methods: In the present study nine adults' male rabbits, aged 3 months were used, and divided into three main groups. Group 1: served as a control and received normal saline only. Group II: given a single dose of 0.5mg/kg per week methotrexate orally by cavage needle for 8 weeks. Group III: given 0.5mg/kg of methotrexate orally twice/weekly for 8 weeks. The animals were scarified and the floor of the mouth, check and tongue, were excised and processed for histological study. Results: The epithelium of oral mucosa in the treated groups is thinner than that of the control group with vacuolation in the cytoplasm, fewer and shorter slender papillae ,congestion of the blood vessels in the lamina propria , fatty infiltration and distortion of attachments of mucosa to underlying muscle .The minor salivary glands show loss of normal architecture ,inflammatory cellular infiltration, disarrangements of acini, and vacuolation in the acinar cells .The dorsal surface of the tongue showed an epithelial atrophy, with loss of the lingual papillae . The lamina propria showed short papillae, inflammatory cellular infiltration and congestion of blood vessels, as well as considerable distortion of arrangements in the musculature of the tongue. Conclusion: weekly administrations of methotrexate produce dramatize histological changes in the oral tissues.