Tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine, is believed to play an important role in multiple sclerosis (MS) pathogenesis. The objective of this study was to determine whether sequence variation in the TNF-alpha gene is associated with MS. Bi-allelic polymorphisms in the TNF-alpha promoter region (TNF-alpha -238 and -308) and microsatellite TNF-alpha were previously reported. We investigated these polymorphisms in 74 French patients with MS, compared with 75 controls. No significant differences regarding the TNF-alpha -238 and -308 polymorphisms were observed between MS patients and controls. Allele frequency for the a11 allele is in very significant association (P<0.0001) with MS, due in part to the association of the a11 allele with the HLA-DRB1*15 allele in patients.