Variation in the genes encoding the interleukin (IL) 7 and IL2 receptor alpha chains (IL7RA, IL2RA) was recently found associated with multiple sclerosis (MS). We evaluated the role of these two genes in a large German MS case-control cohort. Five single nucleotide polymorphisms (SNPs) in IL7RA and four in IL2RA were genotyped in 1319 MS patients and 908 controls by means of restriction enzyme digestion or TaqMan assays and subsequently evaluated for association with MS. IL7RA expression was measured via quantitative real time PCR in 24 subjects. We replicated the association of exon 6 variation (rs6897932) in IL7RA with MS. Yet, this association was only found in patients with primary progressive (pp) or secondary progressive (sp) disease course (p=0.0004). Expression analysis did not show differences in IL7RA expression depending on genotypes at this locus, while reduced expression of the soluble receptor was observed in patients with pp and sp MS irrespective of genotype. In the IL2RA gene, significant associations of SNPs in introns 3 and 7 with MS subtypes were obvious. Together these results confirm involvement of polymorphisms in the IL7RA and IL2RA genes in MS pathogenesis and suggest that IL7RA variation may primarily affect chronic disease courses.