Urocortin 1 (UCN) and adrenomedullin (AM) are two neuropeptides that have emerged as potential endogenous anti-inflammatory factors based on their production by and binding to immune cells. Because human septic shock involves excessive inflammatory cytokine production, we investigated the effect of UCN and AM in the production of inflammatory mediators and their therapeutic actions in two models of septic shock. Both peptides down-regulated the production of inflammatory mediators by endotoxin-activated macrophages. The administration of UCN or AM protected against lethality after cecal ligation and puncture or after injection of bacterial endotoxin and prevented septic shock-associated histopathology, such as infiltration of inflammatory cells and intravascularly disseminated coagulation in various target organs. The therapeutic effect of UCN and AM was mediated by decreasing the local and systemic levels of a wide spectrum of inflammatory mediators, including cytokines, chemokines, and the acute phase protein serum amyloid A. Importantly, UCN or AM treatment was therapeutically effective in established endotoxemia. In conclusion, UCN and AM could represent two multistep therapeutic agents for human septic shock to be used in combination with other immunomodulatory agents or complementary as anti-inflammatory factors to other therapies.