We have analyzed the distribution of tumor necrosis factor (TNF) a and -b microsatellite alleles in HLA-DQ and -DR typed Swedish patients with multiple sclerosis (MS) (n = 122) and ethnically matched control subjects (n = 178). We found significant differences in the frequencies of TNFa and TNFb alleles between patients and controls. TNFaII was significantly associated with MS. This was also the case for the combination of TNFaII with TNFb4. However, TNFaII (alone or in combination with TNFb4) did not show any disease association independent of DQA1*0102/ DQB1*0602/DR2, whereas the previously reported strong association with HLA-DQA1*0102/DQB1*0602/DR2 in Scandinavian populations was confirmed. Therefore the association of TNFaII (and TNFb4) is most likely secondary to the increase of DQA1*0102/DQB1*0602/DR2 in MS patients. The proportion of TNFa6 positive individuals was lower among DR2-negative MS patients than among DR2-negative controls (P = 0.08). Since the presence of the TNFa6 allele correlates with low TNF alpha production in response to lipopolysaccharide, it could be speculated that DR2-negative MS patients have an increased risk of being high TNF alpha producers in response to exogenous stimuli.