We have investigated TNF microsatellite polymorphisms in SLE and their association with both HLA class II alleles and disease expression. A total of 91 Caucasoid SLE and 109 matched Caucasoid controls were recruited for this study. TNF microsatellites a, b and d were typed using fluorescent based semi-automated gene scanning. TNF a2, b3 and d2 allele frequencies were significantly increased in the SLE group compared to controls. These alleles were found to be part of an extended HLA-DRB1*0301 haplotype and have previously been associated with high TNF-alpha production. When the SLE group was analyzed according to presentation of certain clinical features, photosensitivity and Raynaud's phenomenon, the frequency of these alleles (TNF a2, b3 and d2) were also significantly increased. No significant increase in the allele frequencies of TNF a2, b3 and d2 was demonstrated in the group of patients with renal involvement. These data suggest that TNF microsatellite alleles are not independent of HLA associations in SLE and may be important in the expression of certain clinical features in SLE.