OBJECTIVE Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease often clustered in families. We investigated the association between MHC haplotypes and SLE in multicase Caucasian families. METHODS Ten consecutive families with 2 or more patients with SLE, in total 27 patients among 66 individuals, were studied. MHC haplotypes were determined by typing for HLA-A, B, C, DR, and DQ by serological and DNA methods. Complotypes were determined by protein typing and C4 gene polymorphism by DNA analysis. RESULTS Fifty-four independent MHC haplotypes were found. Ten of the 31 haplotypes in the patients with SLE were examples of the extended haplotype [HLA-B8,SC01,DR17]. Six of these were found in 2 or more patients with SLE within the same family. All the 14 SLE sib-pairs in the families shared at least one haplotype and in 9 of the sib-pairs the shared haplotype was [HLA-B8,SCO1,DR17]. Three SLE associated haplotypes were [HLA-B7,SC31,DR15]. Four of the 27 patients with SLE were C4A deficient. Two C2 deficient siblings were homozygous for the haplotype [HLA-B18,S042,DR15]. CONCLUSIONS We demonstrate that a very limited number of MHC haplotypes are associated with familial SLE. The haplotype [HLA-B8,SCO1,DR17] was closely related with the disease. There was no evidence suggesting familial SLE constitutes a disease subset. Determination of MHC haplotypes in multicase families is of value for assessment of disease susceptibility.