We found high levels, defined as an optical density (OD) >0.5 on ELISA, of auto-Abs against IFN-α2, IFN-β, and/or IFN-ω in 147/441 (33%) patients with WNVD (126/348 [36%] with neuroinvasive disease and 21/93 [23%] patients hospitalized without documented neurological disease). This evidence concerns the gene IFNB1 and nervous system disorder.