Multiple sclerosis (MS) is a chronic inflammatory CNS disorder, resulting in progressive neurological dysfunction. The disease has a higher incidence in Caucasian Americans (CA) than African Americans (AA); however, the latter may have a more aggressive disease course. We used cluster analysis to determine whether there is a difference in disease progression between the races and whether the APOE AND APOC1 genotypes influence the disease progression. AA female patients were younger and had a higher progression index and MS severity score than CA female MS patients. AA females who were APOE 4/4, 2/4, or 2/3 and APOC1 AA had a younger age-of-onset, had primarily a relapsing remitting disease course, with a higher progression index and MS severity score, as assessed by cluster analysis. Cluster analysis also indicated that CA female patients were of two groups. One group was younger, had the APOE 3/3 genotype with relapsing remitting less severe disease. The second CA group was older, had the APOE 3/4 or 2/3 genotypes with more of the secondary progressive more severe disease phenotype. Thus, the AA MS female patients who were APOE 4 carriers had an earlier age-of-onset and more severe disease course than CA MS female patients.