In vitro studies suggest that the type I interferon (IFN) signature seen in most lupus patients results from Fcγ receptor-mediated uptake of nucleic acid-containing immune complexes by plasmacytoid dendritic cells and engagement of endosomal Toll-like receptors. The aim of this study was to reexamine the pathogenesis of the IFN signature in vivo.Lupus was induced in mice by injecting pristane. Some mice were treated with normal immunoglobulin or with cobra venom factor to deplete complement. The IFN signature was evaluated by polymerase chain reaction. The IFN signature also was determined in C4-deficient patients and control subjects.Wild-type C57BL/6 mice with pristane-induced lupus developed a strong IFN signature, which was absent in immunoglobulin-deficient (μMT), C3These studies define previously unrecognized roles of natural IgM, complement, and complement receptors in generating the IFN signature in lupus.