The immunoregulatory cytokine interleukin6 (IL6) acts in a pro- and anti-inflammatory fashion. Synthesized by myeloid cells, fibroblasts and endothelial cells, IL6 on target cells, binds to the IL6 receptor (IL6R) and signals via complex formation with the ubiquitously expressed gp130 receptor. Paradoxically, most cells that respond to IL6 during inflammatory states do not express the IL6R and are themselves not directly responsive to the cytokine. A naturally occurring soluble form of the IL6R renders all cells responsive to IL6. This alternative signaling process is called IL6 transsignaling. Here we developed a transgenic strategy based on the overexpression of the soluble form of gp130, which specifically blocks all IL6 responses mediated by the soluble IL6R but does not affect IL6 responses via the membrane bound IL6R. In these mice, inflammatory processes are blocked as in IL6^−/− mice, strongly arguing for a major role of the soluble IL6R during inflammation in vivo.