Histamine is a biogenic amine that mediates multiple physiological processes, including immunomodulatory effects in allergic and inflammatory reactions, and also plays a key regulatory role in experimental allergic encephalomyelitis, the autoimmune model of multiple sclerosis. The pleiotropic effects of histamine are mediated by four G protein-coupled receptors, as follows: Hrh1/H 1R, Hrh2/H 2R, Hrh3/H 3R, and Hrh4/H 4R. H 4R expression is primarily restricted to hematopoietic cells, and its role in autoimmune inflammatory demyelinating disease of the CNS has not been studied. In this study, we show that, compared with wild-type mice, animals with a disrupted Hrh4 (H 4RKO) develop more severe myelin oligodendrocyte glycoprotein (MOG) 35-55-induced experimental allergic encephalomyelitis. Mechanistically, we also show that H 4R plays a role in determining the frequency of T regulatory (T R) cells in secondary lymphoid tissues, and regulates T R cell chemotaxis and suppressor activity. Moreover, the lack of H 4R leads to an impairment of an anti-inflammatory response due to fewer T R cells in the CNS during the acute phase of the disease and an increase in the proportion of Th17 cells.