Multiple sclerosis (MS) susceptibility is characterized by maternal parent-of-origin effects and increased female penetrance. In 7796 individuals from 1797 MS families (affected individuals n = 2954), we further implicate epigenetic modifications within major histocompatibility complex (MHC) class II haplotypes as mediating these phenomena. Affected individuals with the main MS-associated allele HLA-DRB1*15 had a higher female-to-male ratio versus those lacking it (P = 0.00023). Distorted transmission of MHC haplotypes by both parent-of-origin and gender-of-affected-offspring was most evident in the maternal HLA-DRB1*15 transmission to affected female offspring (OR = 3.31, 95% CI = 2.59-4.24) contrasting with similarity among maternal transmission to affected male offspring (OR = 2.13, 95% CI = 1.44-3.14), paternal transmissions to affected female (OR = 2.14, 95% CI = 1.64-2.78) and male (OR = 2.16, 95% CI = 1.37-3.39) offspring. Significant parent-of-origin effects were observed in affected females (maternal: P = 9.33 x 10(-42); paternal: P = 1.12 x 10(-15); comparison: P = 0.0014), but not in affected males (maternal: P = 6.70 x 10(-8); paternal: P = 2.54 x 10(-6); comparison: P = 0.95). Conditional logistic regression analysis revealed further differential risk of HLA diplotypes. Risks for HLA-DRB1*15 and likely for other HLA-DRB1 haplotypes were restricted by (i) parent-of-origin, (ii) gender-of-offspring and (iii) trans epistasis in offspring. These findings may illuminate the gender bias characterizing autoimmunity overall. They raise questions about the concept of restricted antigen presentation in autoimmunity and suggest that gender-specific epigenetic interactions may be the driving forces behind the MHC haplotypic associations. Haplotype-specific epigenetic modifications at MHC class II and their decay appear to be at the heart of MS pathogenesis and inheritance of risk, providing the focus for gene-environment interactions that determine susceptibility and resistance.