Objective: To investigate the association between apolipoprotein E (APOE) polymorphisms and the progression of MS. Methods: We investigated 428 subjects affected by clinically defined MS, with a disease duration of at least three years. We collected data concerning the age at onset of MS, clinical type, disease duration and disability according to the expanded disability status scale (EDSS). We also calculated the progression index (PI) to evaluate disease progression. APOE genotyping and the -491 A/T polymorphism of the APOE promoter were determined. Results: No association was observed between the APOE ε4 allele and clinical characteristics of our study population. We also investigated the -491 A/T APOE promoter polymorphism in 236 MS subjects and did not find any association between the -491 A/T polymorphism and the selected clinical variables. Conclusions: In our population the APOE ε4 allele and the -491 A/T APOE promoter polymorphism are not associated with a more rapid course of MS.