Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with significant morbidity and mortality, characterized by remarkable clinical variability with unknown etiology. Genetic contribution to the development of SLE is well established. Recently, we found evidence (P<0.004) of linkage at 16p13 and 16q12-13 in a genome scan based on 37 Hispanic families. The main objective of this study is to replicate and confirm the linkage at these two genomic locations in two large independent replication data sets designated as, group-1 and group-2, consisting of 172 and 120 multiplex SLE families, respectively. We have found a significant evidence of linkage with high heterogeneity (HLOD=4.85, alpha=35%) at 16q12-13 in group-2. Other independent research groups also reported the SLE susceptibility at or close to 16q12-13 previously. Therefore, independent published reports, together with our initial linkage with Hispanics and followed by significant evidence from group-2, provide a strong and confirmed evidence for an SLE susceptibility locus at 16q12-13.