As the understanding of the autoimmune inflammatory response in multiple sclerosis (MS) expands, polymorphic genes involved in this process become possible candidates that may determine the severity of disease. Therefore, three candidate genes DRB1*1501, CCR5 and apolipoprotein E (APOE) were examined in a population-based patient sample (n = 70) to assess an association between disease progression measured by clinical disability and MRI parameters. The total lesion area (TLA) on T2-weighted images was measured with a semi-automated threshold technique. Patients with the CCR5delta32 allele showed a non-significant trend towards a smaller lesion burden (TLA/years duration), but were not associated to a milder EDSS/years duration. Our data support previous assumptions of a modulation of severity in MS by the CCR5delta32 genotype, which may convey less inflammation and tissue destruction. Carriers of the DRB1*1501 and APOE-epsilon4 allels did not reveal more severe disease progression, neither by the EDSS/years of duration nor by the TLA/years duration. This study was performed on a population-based sample in a genetically homogeneous Danish population but, due to the limited number of patients examined, weak associations between candidate genes and disease variables cannot be excluded.