To evaluate the association of alleles of regions having regulatory potential in the IL-6 gene, with SLE, the AT-rich minisatellite in the 3′ flanking region and the 5′ promoter-enhancer of the IL-6 gene were genotyped by PCR-and RFLP-based methods. The AT-rich minisatellite allele distribution pattern was significantly different in SLE (n= 146) as compared to 139 controls (χ 2 7= 48.97, P= 0.001, Caucasians; and χ 2 7= 19.93, P= 0.006, African-Americans). In either race, short allele sizes (⩽ 792 bp) were seen exclusively in SLE patients (P= 0.001), whereas the 828-bp allele was over-represented in controls (P= 0.015 and 0.002). In contrast, there was no preferential association of SLE with G/C alleles in the 5′ region of the IL-6 gene. Furthermore, our results suggest that the 3′ minisatellite alleles have biological significance:(1) B lymphoblastoid cells of patients having one or two SLE-associated alleles secreted IL-6 in 3-to 4-fold higher levels than non-allelic cells (P< 0.05);(2) higher percentages (approximately 4-fold) of il-6 positive monocytes were observed in individuals having sle-associated il-6 alleles;(3) in lupus patients having sle-associated minisatellite alleles, il-6 mrna stability was significantly enhanced.