Structural polymorphisms (L263P, M313V, and S331P) in the third intracellular loop of the murine histamine receptor H1 (H 1R) are candidates for Bphs, a shared autoimmune disease locus in experimental allergic encephalomyeiitis and experimental allergic orchitis. The P-V-P haplotype is associated with increased disease susceptibility (H 1RS) whereas the L-M-S haplotype is associated with less severe disease (H1RR). In this study, we show that selective re-expression of the H1RS allele in T cells fully complements experimental allergic encephalomyeiitis susceptibility and the production of disease-associated cytokines while selective re-expression of the H1RR allele does not. Mechanistically, we show that the two H1R alleles exhibit differential cell surface expression and altered intracellular trafficking, with the H1RR allele being retained within the endoplasmic reticulum. Moreover, we show that all three residues (L-M-S) comprising the H1RR haplotype are required for altered expression. These data are the first to demonstrate that structural polymorphisms influencing cell surface expression of a G protein-coupled receptor in T cells regulates immune functions and autoimmune disease susceptibility.