The objective of this study was to determine whether sequence variation in the tumor necrosis factor alpha (TNF alpha) gene is associated with MS course and severity in Olmsted County, MN. The severity and temporal course of MS are heterogeneous. Genetic factors may play a role in determining the course of MS. TNF alpha expression is temporally associated with exacerbations of MS and is increased in individuals with progressive disease. The entire TNF alpha gene was amplified by polymerase chain reaction in 78 MS patients and in 39 patients with schizophrenia. Denaturation finger-printing, a modification of direct sequencing that detects virtually all genetic polymorphisms, was performed for four regions spanning the functionally significant portions of the gene, including the promoter region. Polymorphisms were confirmed by complete sequencing. The severity and temporal course of MS were compared in those with wild-type versus variant alleles. Four sequence changes were detected, three of which occurred in MS patients. None occurred in a protein-encoding sequence. Neither of the two most common sequence variants were associated with disease severity or temporal course. Genetic variation of the TNF alpha gene is not associated with variation in the course or long-term outcome of MS in this population-based sample.