Interleukin (IL)‐6 binds to IL‐6R and the complex of IL‐6 and IL‐6R associates with the receptor subunit gp130, which initiates signaling. gp130 is expressed on all cells. IL‐6R is cleaved by the ADAM17, generating a soluble IL‐6R (sIL‐6R). The sIL‐6R binds IL‐6 and the complex of IL‐6 and sIL‐6R binds to gp130 even on cells that do not express IL‐6R. This process, which has been called IL‐6 trans‐signaling, increases the spectrum of target cells for IL‐6. We generated a protein, sgp130Fc, which inhibits IL‐6 trans‐signaling without affecting IL‐6 classic signaling. Using the sgp130Fc protein we demonstrated that IL‐6 classic signaling is antiinflammatory and protective, whereas IL‐6 trans‐signaling is proinflammatory. Blocking IL‐6 trans‐signaling does not compromise the defense of the body against bacterial infections. We suggest that sgp130Fc is a superior agent as compared to IL‐6 or IL‐6R antibodies to block IL‐6. The sgp130Fc protein is in phase II clinical trials.