The purpose of this study was to investigate the relation between APOE genotype and Multiple Sclerosis (MS) in a genetically homogeneous population. We examined 240 patients consulting the MS-clinic during a period of 3 years (1996 - 1999). The mean age of the patients was 41.7 years (range 19 - 80 Y, SD 10.0 Y). As a measure of the progression rate (PR) the last registered Expanded Disability Status Scale (EDSS) score was divided by the time span (years) from disease onset until the latest assessment. The APOE genotype was determined from saliva and/or blood samples using PCR-techniques. The prevalence of different APOE genotypes was compared with the allele-distribution in a population of 361 persons from a Danish cross-sectional population study. The frequency of APOE-epsilon 4/epsilon 4 homozygotes was significantly higher in the MS-group as compared to controls (P<0.05, odds ratio: 2.3), whereas the frequency distribution of other genotypes did not differ significantly. The rate of progression was significantly faster in the APOE-epsilon 4/epsilon 4 homozygotes compared to other genotypes in the MS group (P<0.05). This study suggests that the APOE-epsilon 4/epsilon 4 homozygotes have an increased risk of developing MS. MS patients with the APOE-epsilon 4/epsilon 4 allele may also have an increased rate of disease progression. Multiple Sclerosis (2000) 6 226 - 230