In multiple sclerosis (MS), alpha(4)beta(1) integrin, also known as Very Late Antigen 4 (VLA4), facilitates migration of leukocytes across the blood brain barrier. Several studies suggest that expression of alpha(4) integrin may be increased in MS patients compared to controls, and down-regulation or antagonism of alpha(4) integrin may be associated with immunomodulatory treatment success. We analysed association of 13 single nucleotide polymorphisms (SNPs) in the gene encoding alpha(4) integrin (ITGA4) with susceptibility to MS in two distinct populations comprising cases and controls from the Basque Country in northern Spain (352 patients; 235 controls) and Nordic countries (1119 patients; 1235 controls). Carriage of the C allele of the ITGA4 promoter SNP rs1449263 was independently and weakly increased in MS patients from each population compared to respective controls (P = 0.037 in Basque; and P = 0.042 in Nordic cohorts), though these associations were lost upon application of permutation correction. Meta-analysis of rs1449263*C carriage revealed a Mantel-Haenszel common OR of 1.26 (95% CI 1.06-1.49; P = 0.0069). Though our data only modestly argue for a role of ITGA4 in determining susceptibility to MS, we suggest that further examination of this gene, particularly the promoter region, is warranted.