Abbreviations used: CNS, central nervous system; EAE, experimental autoimmune encephalomyelitis; LNC, LN cell; MOG, myelin oligodendrocyte glycoprotein; PLP, proteolipid protein.The online version of this article contains supplemental material. Most autoimmune diseases are more common in women than in men. This may be caused by differences in sex hormones, sex chromosomes, or both. In this study, we determined if there was a contribution of sex chromosomes to sex differences in susceptibility to two immunologically distinct disease models, experimental autoimmune encephalomyelitis (EAE) and pristane-induced lupus. Transgenic SJL mice were created to permit a comparison between XX and XY within a common gonadal type. Mice of the XX sex chromosome complement, as compared with XY, demonstrated greater susceptibility to both EAE and lupus. This is the fi rst evidence that the XX sex chromosome complement, as compared with XY, confers greater susceptibility to autoimmune disease.