Background: Fluoride poisoning results from drinking fluoride rich ground water which is an important source of water supply throughout the world. Recently, resveratrol has been used as anti-oxidative, anti-inflammatory agent and it is a naturally occurring polyphenol present in grapes and red wine. Aim of the work: Evaluation of protective role of resveratrol against sodium fluoride (NaF) toxicity on the spleen. Materials and methods: 40 adult male albino rats were used in this work. The rats were divided into: Group I: This group consists of 10 rats which did not receive any treatment. Group II: formed of 10 rats which were given 30 mg/kg B.W resveratrol once daily for 30 days orally by gastric tube. Group III: (NaF treated group): consists of 10 rats which were given 10mg/kg B.W of NaF dissolved in 2.5 ml distilled water once daily for 30 days orally by gastric tube. Group IV: (NaF and resveratrol treated group): formed of 10 rats which were given10 mg/kg B.W of NaF and 30 mg/kg B.W of resveratrol once daily for 30 days by gastric tube. At the end of experiment the rats were sacrificed and peripheral blood samples were taken for neutrophils, monocytes and lymphocytes count and oxidative markers study then spleen tissues were taken for histo-pathological and immunohistochemical staining techniques. Results: NaF possessed immune toxic effect on the architecture of the spleen in the form of decreased the diameter and atrophy of lymphoid follicles of white bulb of the spleen and red bulb degeneration and these changes were improved after using the resveratrol. Conclusion: prolonged exposure to NaF can cause histopathological changes in the spleen structure which cause decreased in immune response and. resveratrol has the ability to ameliorate the changes which caused by NaF.