Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system in which histamine (HA) and its receptors have been implicated in disease pathogenesis. HA exerts its effects through four different G protein-coupled receptors designated H1-H4. We previously examined the effects of traditional single HA receptor (HR) knockouts (KOs) in experimental allergic encephalomyelitis (EAE), the autoimmune model of MS. Our results revealed that H1R and H2R are propathogenic, while H3R and H4R are antipathogenic. This suggests that combinatorial targeting of HRs may be an effective disease-modifying therapy (DMT) in MS. To test this hypothesis, we generated H1H2RKO and H3H4RKO mice and studied them for susceptibility to EAE. Compared with wild-type (WT) mice, H1H2RKO mice developed a less severe clinical disease course, whereas the disease course of H3H4RKO mice was more severe. H1H2RKO mice also developed less neuropathology and disrupted blood brain barrier permeability compared with WT and H3H4RKO mice. Additionally, splenocytes from immunized H1H2RKO mice produced less interferon(IFN)-γ and interleukin(IL)-17. These findings support the concept that combined pharmacological targeting of HRs may be an appropriate ancillary DMT in MS and other immunopathologic diseases.