Intercellular adhesion molecule-1 (ICAM-1) and its receptors are adhesion molecules that play a key role in the transmigration of inflammatory cells through the blood-brain barrier, one of the earliest events in multiple sclerosis (MS), which leads to demyelination in the central nervous system. To investigate the role of genes encoding ICAM-1 and its receptors, we used a strategy of genetic linkage and association in 439 case-parent MS families of French origin, well characterized according to HLA status and severity. We demonstrate that the genes encoding ICAM-1 receptors do not influence MS susceptibility or severity. ICAM-1 had a modest, but significant effect on MS genetic susceptibility, independent of HLA and disease severity. We observed a rare, and an as yet unreported, ICAM-1 gene haplotype defined by amino acids K469 and R241 that was never transmitted to patients suggesting a protective effect against MS in our population.