A recent meta-analysis revealed the contribution of the SIGLEC6 locus to the risk of developing systemic lupus erythematosus (SLE). However, no specific Siglec (sialic acid-binding immunoglobulin-like lectin) genes (Siglecs) have been implicated in the pathogenesis of SLE. Here, we performed in silico analysis of the function of three major protective alleles in the locus and found that these alleles were expression quantitative trait loci that enhanced expression of the adjacent SIGLEC12 gene. These data suggest that SIGLEC12 may protect against the development of SLE in Asian populations. Consistent with human genetic data, we identified two missense mutations in lupus-prone B6.NZMSle1/Sle2/Sle3 (Sle1-3) mice in Siglece, which is the murine Siglec with the greatest homology to human SIGLEC12. Since the mutations resulted in reduced binding of Siglec E to splenic cells, we evaluated whether Siglece-/- mice had SLE phenotypes. We found that Siglece-/- mice showed increased autoantibody production, glomerular immune complex deposition and severe renal pathology reminiscent of human SLE nephropathy. Our data demonstrate that the Siglec genes confer resistance to SLE in mice and humans.