Variation in the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) gene plays a significant role in determining susceptibility to autoimmune thyroid disease and type 1 diabetes. Its role in multiple sclerosis is more controversial. In order to explore this logical candidate more thoroughly, we genotyped 771 multiple sclerosis trio families from the United Kingdom for the 3' untranslated region variable number tandem repeat, the CT60 single nucleotide polymorphism (SNP) and five haplotype-tagging SNPs. No individual marker or common haplotype showed evidence of association with disease. These data suggest that any effect of CTLA-4 on multiple sclerosis susceptibility is likely to be very small.