In chronic kidney disease, systemic inflammation is common and associated with mortality. The present study demonstrates that fibroblast growth factor 23 (FGF23) contributes to uremic inflammation by increasing hepatic expression and secretion of inflammatory cytokines. FGF23 binds to hepatic FGFR4, inducing calcineurin/nuclear factor of activated T-cell signaling, resulting in increased expression of interleukin 6 and C-reactive protein. The proinflammatory effects of FGF23 are inhibited by an isoform-specific FGFR4 blocking antibody and by cyclosporine, a calcineurin inhibitor.