In the present study, we used Cyld−/− mice with a normal immune system and demonstrate that CYLD prevented survival from severe systemic listeriosis by (i) inhibiting protective NF-κB-dependent innate immune responses, (ii) impairing IL-6-induced STAT3 activation due to deubiquitination of K63-ubiquitinated STAT3 and (iii) reduction of STAT3-dependent fibrin production. The gene discussed is IL6; the disease is listeriosis.