Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), expressed on activated T cells, binds to B7 molecules on antigen-presenting cells. Signaling via CTLA-4 results in downregulation of ongoing T-cell clonal expansion. A single-nucleotide polymorphism (SNP) in exon 1 of CTLA4 is associated with susceptibility to several autoimmune diseases, including multiple sclerosis (MS). In this two-stage study, we investigated whether haplotypes composed of exon 1-SNP alleles and alleles of a promoter-region SNP influence age at onset, disease severity and disease course in MS. In stage 1, deviations in CTLA4 haplotype frequencies were observed in patients subgrouped by course; in stage 2, none of these original associations were confirmed.