A large body of research supports a multifactorial cause in multiple sclerosis (MS), with an underlying genetic susceptibility likely acting in concert with undefined environmental exposures. Here, we used a highly efficient multilocus genotyping assay to study single nucleotide polymorphisms representing variation in 34 genes from inflammatory pathways in a well-characterized MS familial data set. Evidence of transmission distortion was present for several polymorphisms. Results for the NOS2A locus (exon 10 C/T, D346D) on chromosome 17q11 remained significant after correction for multiple testing and were reproduced in a second independent African American MS data set. In addition, linkage to a NOS2A promoter region polymorphism, (CCTTT)(n), was present in a third data set of multicase MS families. Our results provide strong evidence for linkage and association to a new candidate disease gene on chromosome 17q11 in MS and suggest that variation within NOS2A or a nearby locus contributes to disease susceptibility.