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Background: Interferon (IFN) gamma (IFNG) allelic variants are associated with susceptibility to multiple sclerosis (MS) in men but not in women., Objectives: To conduct a high-density linkage disequilibrium association study of IFNG and the surrounding region for sex-associated MS susceptibility bias and to evaluate whether IFNG allelic variants associated with MS susceptibility are associated with expression., Design: Genotype case-control study, quantitative polymerase chain reaction (qPCR), and enzyme-linked immunosorbent assay expression analyses for IFN gamma., Setting: Three independently ascertained populations from the Mayo Clinic, Rochester, Minnesota, Queen's University of Belfast, Belfast, Ireland, and University of Leuven, Leuven, Belgium., Patients: For linkage disequilibrium, 861 patients with MS (293 men and 568 women) and 843 controls (340 men and 503 women) derived from the US (population-based) and the Northern Ireland and Belgium (clinic-based) cohorts were studied. For expression analyses, 50 US patients were selected to enrich for homozygotes and to achieve a balance between men and women., Interventions: Twenty markers were genotyped over the 120-kilobase region harboring IFNG and the interleukin 26 gene (IL26)., Main Outcome Measures: Expression of IFN gamma was evaluated by qPCR and enzyme-linked immunosorbent assay in stimulated peripheral blood mononuclear cells., Results: Multiple markers were associated with MS susceptibility in men but not in women. The sex-specific susceptibility markers, of which rs2069727 was the strongest, were confined to IFNG. Carriers of rs2069727*G had higher expression than noncarriers. The effect of genotype in the qPCR experiments was also evident in men but not in women., Conclusions: IFNG is associated with sex bias in MS susceptibility and with expression of IFN gamma in MS. These observations add to a growing body of literature that implicates an interaction between sex and IFN gamma expression in a variety of disease states.