Systemic lupus erythematosus (SLE) is a complex autoimmune disorder involving at least hormonal, environmental, and genetic factors. Familial aggregation, a 2%-3% sibling recurrence rate, monozygotic twin concordance >20%, association with several candidate genes, as well as the results of five genome scans support a genetic component. We present here the results of a genome scan of 126 pedigrees multiplex for SLE, including 469 sibling pairs (affected and unaffected) and 175 affected relative pairs. Using the revised multipoint Haseman-Elston regression technique for concordant and discordant sibling pairs and a conditional logistic regression technique for affected relative pairs, we identify a novel linkage to chromosome 4p16-15.2 (P=.0003 and LOD=3.84) and present evidence of an epistatic interaction between chromosome 4p16-15.2 and chromosome 5p15 in our European American families. We confirm the evidence of linkage to chromosome 4p16-15.2 in European American families using data from an independent pedigree collection. In addition, our data support the published results of three independent studies for nine purportedly linked regions and agree with the previously published results from a subset of these data for three regions. In summary, results from two new analytical techniques establish and confirm linkage with SLE at 4p16-15.2, indicate epistasis between 4p16-15.2 and 5p15, and confirm other linkage effects with SLE that have been reported elsewhere.