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=l22) and ethnically matched control subjects (n=l78). We found significant differences in the frequencies of TNFa and TNFb alleles between patients and controls. TNFal I was significantly associated with MS. This was also the case for the combination of TNFal I with TNFb4. However, TNFal I (alone or in combination with TNFb4) did not show any disease association independent of DQA 1*01021 DQBI*0602/DR2, whereas the previously reported strong association with HLA-DQAI*0102/DQBI*0602/DR2 in Scandinavian populations was confirmed. Therefore the association of TNFal I (and TNFb4) is most likely secondary to the increase of DQAI*0102/DQBl*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 TNFab allele correlates with low TNFα production in response to lipopolysaccharide, it could be speculated that DR2-negative MS patients have an increased risk of being high TNFα producers in response to exogenous stimuli.