Inflammation participates in the genesis and progression of hypoxic-ischemic brain injury. Interleukin (IL)-1 is a major pro-inflammatory cytokine, which plays a dominant role in hypoxic-ischemic (and postinfectious) brain damage. Abundant evidence reveals the principal involvement of IL-1 over other pro-inflammatory cytokines. IL-1 interacts with the IL-1 receptor I (IL-1RI). The natural IL-1 receptor antagonist (IL-1ra) is a large 17.5-kDa peptide that competes with IL-1 for its binding site on IL-1RI. Recombinant IL-1ra (Kineret) is effective in human inflammatory conditions. However, a number of drawbacks of IL-1ra limit its broader use; these include injection site reactions [70%], broad immunosuppression, and high costs. We hereby report the characterization of a small (peptide) IL-1RI antagonist we developed, namely rytvela (termed 101.10), and its efficacy in models of (gut) inflammation and of newborn hypoxic-ischemic brain injury. Experiments reveal that 101.10 is selective for the IL-1RI and inhibits to a variable extent different effects induced by IL-1. 101.10 is effective in vivo (on systemic as well as oral administration) in established models of inflammation involving IL-1, notably in inflammatory bowel disease, and is superior to dexamethasone. In a rat pup model of hypoxic-ischemic brain injury (Rice-Vannucci model), where IL-1 and IL-1R expression is increased, 101.10 preserved microvascular density, parenchymal integrity, and brain mass. In conclusion, we hereby describe for the first time the discovery of a stable, potent, and effective specific IL-1RI small (peptide) antagonist, namely 101.10 (rytvela), which exhibits allosteric modulatory properties, and is effective in vivo in models of inflammation (known to involve IL-1) and in particular in hypoxic-ischemic newborn brain injury. 101.10 (and small alike compounds) may be suitable alternatives to IL-1ra.