The TNF alpha and beta genes are located between the class I and class III HLA loci and have been implicated in the pathogenesis of multiple sclerosis. We carried out allelic association analysis using four microsatellite markers localised within a 20 kb region around the TNF genes. The study was performed on DNA samples from 189 clinically definite MS patients and 206 normal controls, all of Northern Irish origin. The allele distributions for the TNFa and b markers were significantly different between the MS patients and controls (P = 0.014, df 8 and 0.0019, df 4, respectively). The difference could largely be attributed to increases in the TNFa 118 bp allele and the TNFb 127 bp allele in MS patients, with a conserved MS associated haplotype (130:118:127 TNF d:a:b). Of the 19 patients homozygous for this haplotype, 17 were HLA typed and results suggested that the TNF haplotype association can occur independently of inheritance of DR2. Transmission disequilibrium testing (TDT) also supported the TNFa 118 bp association. These results suggest that in this population TNF is possibly one of the genetic factors contributing to MS susceptibility.