Tumor necrosis factor alpha (TNF alpha) expression is enhanced in patients with active MS and other inflammatory diseases. A guanine-to-adenine polymorphism at position -308 of the TNF alpha promoter region (the TNF2 allele) is associated with increased TNF alpha expression. We evaluated 110 MS patients derived from an Olmsted County, MN, prevalence study. Three other patient cohorts (autoimmune, serious infectious illness, and other neurologic diseases) and matched controls were derived from a Mayo Clinic DNA bank. We used polymerase chain reaction amplification of specific alleles to screen for the TNF2 allele and to determine zygosity. We found one homozygote and 29 heterozygotes in the MS patients. There was no association between the presence of the TNF2 allele and MS or the other disease categories by matched-pair and group analyses.