Systemic lupus erythematosus (SLE) is a chronic, autoimmune disorder influenced by multiple genetic and environmental factors. Linkage of SLE to chromosome 16q12-13 (LOD score=3.85) was first identified in pedigrees collected at the University of Minnesota, and has been replicated in several independent SLE collections. We performed fine mapping using microsatellites to further refine the susceptibility region(s), and the best evidence for linkage was identified at marker D16S3396 (LOD=2.28, P=0.0006). Evidence of association was suggested in the analysis of all families (D16S3094, P=0.0516) and improved to the level of significance (P=0.0106) when only the Caucasian families were analyzed. Subsets of pedigrees were then selected on the basis of clinical manifestations, and these subsets showed evidence for association with several markers: GATA143D05 (renal, P=0.0064), D16S3035 (renal, P=0.0418), D16S3117 (renal, P=0.0366), D16S3071 (malar rash, P=0.03638; neuropsychiatric, P=0.0349; oral ulcers, P=0.0459), D16S3094 (hematologic, P=0.0226), and D16S3089 (arthritis, P=0.0141). Together, these data provide further evidence that an important susceptibility gene(s) for SLE is located at 16q12.