Abstract IFN-α production by pDCs regulates host protection against viruses and is implicated in autoimmune pathology. Human pDCs express high levels of IL-18R, but little is known of its role in pDC function. We report that IL-18R signaling negatively regulates IFN-α production through activation-induced splicing of IL-18Rα in human pDCs. Our data reveal two distinct isoforms of IL-18Rα in human pDCs: the known, full-length receptor (IL-18Rα1) and a novel, truncated variant (IL-18Rα2), which functions as a molecular decoy that competitively inhibits the canonical IL-18Rα1/IL-18Rβ signaling pathway. Whereas NK cells and pDCs both express IL-18Rα1, pDCs express significantly higher levels of IL-18Rα2, resulting in differential responses of these populations to IL-18. Flu exposure increases IL-18Rα1 expression in pDCs, and the blocking of IL-18R enhances pDC production of IFN-α and IP-10; thus, pDCs use activation-induced splicing to regulate IFN-α production in response to flu. These data demonstrate that IL-18R modulates IFN-α release by human pDCs and suggest that IL-18R signaling may represent a promising therapeutic target.