HLA-A, -B, -C, -DR, -DQ antigens were studied in 11 multiplex MS families, 11 single-case MS families and 100 healthy subjects. The HLA DR4 was the most frequent antigen in all MS patients (p = 0.015). When the antigenic frequency in index familial cases was compared with that in single cases, the DR4 antigen was found to be more frequent (p = 0.01) in familial cases only. Furthermore, when the DR4 antigen was excluded from the analysis, we observed an increase in DR2 (p = 0.11) only in the familial MS cases. These results can be compatible with a multifactorial hypothesis according to which the HLA genes have an important role in MS susceptibility in familial cases.