Introduction: Dysfunction in the integrity of the blood-brain barrier (BBB) is one of the earliest symptoms of MS. The Semaphorin 4D protein and its receptor Plexin B1 play an important role in maintaining the integrity of the blood-brain barrier and the progression of MS. Therefore, the purpose of the present study is to investigate the role of aerobic and resistance exercise on the protein levels of Semaphorin4D-Plexin B1 and the integrity of the blood-brain barrier in mice with Experimental autoimmune encephalomyelitis, an animal model of MS. Materials and Methods:40 female C57BL6 mice were randomly divided into four groups with n= 10 in each group. The EAE group was induced by injection of MOG35-55 peptide, the second group had saline injection (healthy control group), and the third and fourth groups, after the induction of EAE performed resistance and aerobic exercise, 5 consecutive days in a week, for 4 weeks. On the 30th day after induction (chronic period of the disease), mice were anesthetized with ketamine and xylazine injection and brain tissue was removed. Semaphorin D4 and plexin B1 protein levels were measured by immunohistochemistry and blood-brain barrier integrity was measured by Evans blue test. Result: The findings of the present study showed that EAE induction significantly increased the protein levels of Semaphorin 4D (P=0.001), Plexin B1 (P=0.001) and permeability of the blood-brain barrier (P=0.0001). Four weeks of aerobic and resistance exercise decreased the protein levels of Semaphorin 4D, Plexin B1 and permeability of the blood-brain barrier (P≥0.05) and there was no significant difference between the two types of exercise (P≤0.05).Conclusion: Aerobic and resistance exercise can prevent the destruction of the blood-brain barrier by reducing the levels of Sema4D- PlexinB1 in the brain.