We have investigated the association of multiple sclerosis (MS) with polymorphisms in the IL4R gene in 332 single-case MS families. IL4R encodes a subunit of the interleukin-4 receptor, a molecule important for T-cell development and differentiation, and is a gene shown to be associated with immune-related diseases such as asthma and type I diabetes. By genotyping two promoter and eight coding IL4R SNPs and identifying haplotypes (complex alleles) in the MS families, stratified for HLA genotype, we have observed evidence of the association of the IL4R gene to MS. In particular, we have identified a specific susceptibility haplotype, and observe that the risk is conferred primarily to individuals not carrying the high MS-risk HLA DR2 (DRB1(*)1501-DQB1(*)0602) haplotype (nominal P=0.009). These findings suggest a potentially important role for the IL4R gene in predisposition to MS, and provide further evidence of its relevance as a candidate gene for immune-related diseases.