A growing body of evidence has shown that the human immunodeficiency virus (HIV) infection is associated with a significantly decreased risk of developing multiple sclerosis (MS) in patients with acquired immunodeficiency virus (AIDS). It is thought that two mechanisms are in charge of protection against MS, which include immunosuppression induced by chronic HIV infection (depletion of CD4+T cells) and antiretroviral medications. HIV-1 encodes several regulatory (Tat and Rev) and accessory (Vpr, Vif, Vpu, and Nef) proteins that have immunosuppressive and immunomodulatory properties. HIV-1 Tat protein is a strongly immunosuppressive agent and can cross the blood-brain barrier (BBB). In this study, we examined the effect of HIV-1 Tat, which is classified into clade B and C, on inflammation, gliosis, apoptosis, and behavioral function in a murine model of MS called experimental autoimmune encephalomyelitis (EAE). For this aim, mice were immunized with myelin oligodendrocyte glycoprotein 35-55 (MOG35-55), followed by pertussis toxin to induce paralysis in EAE mice. After the induction of EAE in mice, the animals intraperitoneally received serial doses of HIV-1 Tat clade B and C (5, 10, and 20g/kg body weight) when the early clinical manifestations of EAE were initiated. The results showed that the administration of both clades of the Tat protein led to a marked decrease in the clinical score of EAE mice, as well as improvement in motor-neuron functions. In line with this, Tat considerably reduced the number of apoptotic cells in the sacral region of the spinal cord through the upregulation expression of the Bcl-2 protein. Besides, proinflammatory cytokines such as, IFN-, TNF-, IL-6, and IL-17 were significantly diminished in the serum and spinal cord of EAE mice receiving HIV-1 Tat clade B and C. Conversely, anti-inflammatory cytokines, including IL-10 and IL-4 were elevated in the serum and spinal cord of EAE mice receiving HIV Tat clade B and C when compared with the control group. The immunohistochemical analysis indicated that HIV-1 Tat clade B and C mitigated microgliosis and astrogliosis. The flow cytometry analysis demonstrated that the number of Th1 and Th17cells was significantly decreased in response to TAT administration while the frequency of Th2 cells was markedly increased in the peripheral blood of mice with EAE without influencing the number of T regulatory cells (CD4+CD25+forkhead box protein 3+). It seems that HIV-1 Tat could be a bona fide therapeutic protein for the alleviation of MS since it has beneficial roles in the suppression of neuroinflammation in MS pathology. Copyright 2019. Published by Elsevier B.V.